Comparative Analysis of Primary (3R/4R) versus Secondary (3R + 4R) Tauopathy Strains in Rodent Models: A Systematic Review

Comparative Analysis of Primary (3R/4R) versus Secondary (3R + 4R) Tauopathy Strains in Rodent Models: A Systematic Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Comparative Analysis of Primary (3R/4R) versus Secondary (3R + 4R) Tauopathy Strains in Rodent Models: A Systematic Review Mohamed A. Wafa, Amro K. Barakat, Mostafa Shaheen, Ahmed Tarif, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8090222/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Tauopathies are a heterogeneous group of neurodegenerative disorders characterized by a pathological tau aggregation. Each disorder is defined by distinct isoform content (3R, 4R, or mixed 3R/4R), which dictates cell-type susceptibility, pathologic propagation, and clinical symptomatology. How these strains propagate in vivo will be critical to developing translational models and therapies. Methods Following SWiM guidelines, we performed a systematic review with the protocol registered on PROSPERO (CRD420251053445). PubMed, Scopus, and Web of Science (inception - May 2025) searches identified studies directly comparing human brain-derived primary and secondary tau seeds in rodent models. Inclusion criteria required stereotactic intracerebral inoculation, comparable protocols, and reporting of inclusion burden, propagation, or isoform recruitment. SYRCLE tool was employed to assess the risk of bias. Results From the 1,437 screened records, 8 studies were eligible. Propagation in various rodent models was strain consistent: 4R-dominant seeds (CBD, PSP) selectively induced glial inclusions, while mixed AD-derived seeds induced neuronal neurofibrillary tangles with associated neurotoxicity. Isoform-selective recruitment, protease resistance to cleavage at particular sites, and amyloid-binding provided biochemical counterparts of tropism. Serial passage experiments confirmed heritability of strain features. Functional consequences included synaptic dysfunction, gliosis, and neuronal loss, whose spread patterns were host genotype- and time-of-observation-dependent. Risk-of-bias was mixed, with frequent unclear domains. Conclusion These findings support a two-way model in which tau strain conformation dictates cellular tropism, and host biology controls magnitude and distribution, and reinforce the prion-like model of tau transmission. Future work needs to prioritize standardized protocols, advanced humanized models, and multimodal functional readouts. Figures Figure 1 1. Introduction Tau, a microtubule-associated protein, is of crucial significance to neuronal axons as it stabilizes microtubular networks necessary for intracellular transport and cytoskeletal stability ( 1 ). Alternative splicing of the MAPT gene produces six isoforms in the adult human central nervous system that differ primarily in the presence of three (3R) or four (4R) microtubule-binding repeat domains ( 1 ). Pathologically, abnormal post-translational modifications, hyperphosphorylation, induce the dissociation of tau from microtubules. It aggregates to form insoluble paired helical filaments (PHFs), which further mature to neurofibrillary tangles (NFTs) ( 2 ). NFTs are a pathognomonic neuropathological lesion in tauopathies, a family of heterogeneous neurodegenerative diseases that are defined by progressive neuronal dysfunction and regional brain atrophy ( 3 ). Tauopathies are classified based on the dominant tau isoform found in the inclusions. Primary tauopathies have predominantly 3R or 4R tau deposits, while secondary tauopathies have mixed 3R/4R pathology ( 4 ). Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), for example, are primary 4R tauopathies with widespread glial pathology, including astrocytic plaques and oligodendroglial coiled bodies ( 5 ). Pick’s disease (PiD), by contrast, has predominant 3R tau deposition ( 6 ). Alzheimer’s disease (AD), the most common secondary tauopathy, has mixed 3R/4R pathology mainly in neuronal NFTs ( 7 ). Beyond isoform ratios, these clinicopathological distinctions involve cell-type-specific susceptibility, inclusion morphologies, and biochemical mixtures. As a further point, C-terminal tau fragments truncated at residue N368 are found consistently in AD and PSP but not in CBD, suggesting that these fragments may reflect more basic strain differences involving conformation-dependent proteolytic cleavage ( 8 ). These observations serve as the foundation of the tau strain hypothesis, in which structurally different aggregate conformations ("strains") determine regional tropism, cell susceptibility, and patterns of spread ( 9 ). Templated misfolding is the basis of prion-like trans-synaptic transmission, in which disease-causing tau seeds recruit endogenous tau into enlarging aggregates ( 9 ). In vitro patient extract or synthetic preformed fibril (PFF) assays demonstrate strain-dependent aggregation kinetics within cell models ( 10 ). In vivo assays demonstrate distinct pathologies as well: intracerebral inoculation of CBD-derived tau in transgenic mice seeds oligodendroglial inclusions preferentially, whereas AD-tau seeds seed neuronal aggregates ( 11 ). Genome-edited models expressing endogenous human-like 3R/4R tau ratios also exhibit isoform-specific recruitment, in which PiD seeds spread 3R pathology selectively ( 12 ). Non-transgenic models validate human strain tropism, in which PSP-tau inoculation selectively causes astroglial pathology in the absence of AD-tau exposed animals ( 13 ). Despite these developments, significant methodological constraints exclude direct comparisons between human brain-derived and laboratory-derived strains ( 14 ). Different models or isolation procedures are applied in the majority of studies, and these can suppress native strain properties ( 14 ). Recombinant 4R fibrils, for instance, do not recapitulate robust gliotropism of native CBD-derived strains in PS19 mice ( 15 ) Moreover, regional spreading pattern differences between natural and amplified strains show that procedural artifacts can perturb pathogenic pathways ( 16 ). Therefore, whether synthesized or amplified strains truly represent the neuropathological and biochemical properties of their human-derived counterparts is contentious ( 14 ). This systematic review will seek to clarify these uncertainties by a rigorous meta-analysis of head-to-head contrasts in isogenic models. We anticipate primary seeds to exhibit greater fidelity towards simulating human glial tropism and isoform-selective recruitment, and secondary strains to exhibit attenuated or aberrant propagation dynamics as a consequence of purification or amplification artefacts. By evidence synthesis across harmonized experimental paradigms, this project seeks to clarify strain-specific pathomechanisms and optimize translational strategies against tau propagation. 2. Methods 2.1 Registration and Reporting Standards for the Protocol We pre‑registered our systematic review protocol on PROSPERO (CRD420251053445) on 24 June 2025 after a preliminary scoping search confirmed that no duplicate reviews were underway. The protocol was developed in line with the SWiM (Synthesis Without Meta‑analysis) reporting guidance, which provides structured recommendations for transparently conducting and presenting the narrative syntheses ( 17 ). This framework informed the specification of grouping strategies, synthesis methods, and approaches to reporting heterogeneity. Any amendments to the registered protocol were documented in PROSPERO with corresponding dates and justifications. 2.2 Information Sources and Search Dates Systematic electronic literature searching was performed in these three databases: MEDLINE (via PubMed), Scopus, and Web of Science back to the start of each database through 4 May 2025, when searches were most recently up to date. To identify research from non-standard publication sources, we did not hand‑search reference lists from included articles or similar reviews, conference proceedings, and clinical‑trial registries and the databases for pertinent dissertations or technical reports. All of the references were imported into JabRef for auto‑deduplication; this was then manually verified to ensure that near duplicate records or alternative spellings weren't mistakenly eliminated. 2.3 Search Strategy Striking a balance between sensitivity and specificity, we used controlled vocabulary together with free‑text terms. The central search strategy within PubMed was: ("tau") AND ("aggregation" OR "propagation") AND ("injections" OR "seeding" OR "inoculation") AND ("animal models" OR "mouse" OR "rat") We adapted this search to Scopus and Web of Science, applying validated animal‑study filters and restricting to English‑language, peer‑reviewed journal papers. Complete search strings, including database‑specific syntax and any applied limits, are provided in Supplementary Appendix A. 2.4 Inclusion Criteria Studies were included if they met all of the following: Animal Model : Employed wild‑type or tau transgenic mice (e.g., C57BL/6, PS19, 6hTau). Intervention : Performed stereotactic intracerebral injections of human brain‑derived tau aggregates. Primary seeds were Pick's disease tissue (3R‑tau) and 4R‑tauopathies (PSP, CBD, GGT). Secondary seeds were Alzheimer's disease tissue with mixed 3R + 4R tau. Comparative Design : Performed within‑study, head‑to‑head comparisons of primary vs secondary seeds under matched inoculation protocols and post‑injection intervals. Outcomes : Reported quantitative estimates of tau inclusion burden (percent immunopositive area or counts/mm²) and propagation distance (mm). Secondary outcome measures included 3R/4R isoform ratio and regional neuroanatomic distribution. Publication : Reported in full-text, peer-reviewed English language publications. Exclusion criteria included in vitro or human-only research, non-comparative investigations without quantitative head-to-head comparisons, task-based paradigms, conference abstracts, posters, and review articles. 2.5 Study Selection Following deduplication, titles and abstracts were imported into Rayyan QCRI for blinded title/abstract screening by two distinct reviewers. Disagreements, approximately 13 percent of decisions, were resolved and, if not, adjudicated by a third reviewer. Full texts of studies of potential eligibility were screened against the criteria listed above. A PRISMA flow diagram (Fig. 1 in the Appendix) shows the records screened, assessed for eligibility, and included, and reason for exclusion at each stage. 2.6 Data Extraction and Management We created a structured extraction form in Microsoft Excel, based on Cochrane recommendations and adjusted through pilot exercise on four randomly chosen studies. The following variables were extracted: Animal Characteristics : Species, strain, sex distribution, age at inoculation, housing conditions. Inoculum Information : Source of Tauopathy, isoform composition, methods of extraction and purification, dosage and volume, coordinates of injection, and delivery device. Timing of Experiment : Post-injection time points (days) and intermediate measures. Immunostaining Procedures : Antibody clones, dilutions, antigen retrieval procedures, and threshold criteria. Quantitative Outputs : Inclusion burden measures, extents of spread, 3R/4R ratio, and any accompanying behavioral or biochemical correlates. Study-Level Covariates : Sources of funding, conflict-of-interest statements, ethical approval statements. Two reviewers independently performed data extraction; disagreements were resolved by consensus or, as a last resort, by referral to a third member of staff. 2.7 Risk of Bias and Quality Assessment As the preclinical, animal-study setting, methodological quality was assessed with SYRCLE's risk-of-bias tool for selection, performance, detection, attrition, reporting, and other biases. Two authors independently assessed each domain without knowledge of authorship and journal titles. Disagreements were resolved by consensus or by sending the dispute to a third reviewer. Total risk-of‐bias ratings are presented in Table 2, and raw scores in Supplementary Appendix B. 2.8 Data Synthesis and Thematic Framework Substantial heterogeneity between host genotypes, inoculation regimens, outcome measures, and reporting conventions precluded a formal meta-analysis. Instead, we conducted a thematic narrative synthesis, basing our approach on theoretical models of prion‐like tau propagation, network‐based susceptibility, and isoform‐specific seeding kinetics. Studies were stratified along three main axes: (I) Seed Isoform : 3R vs. 4R vs. mixed 3R + 4R, (II) Host Genotype : Wild-type vs. transgenic, and (III) Timing : Short (< 30 days) vs. long (≥ 30 days) post-injection intervals. We tabulated study characteristics and outcomes within each stratum to facilitate cross‑study comparison. Within each stratum, we summarized results to identify trends in seeding efficiency, regional tropism, and recruitment of isoforms. Where two or more studies reported the same finding, we qualitatively compared effect sizes and placed findings within context of methodological difference, such as: thresholding criteria for immunostaining or anatomical definitions of propagation. 2.9 Subgroup and Sensitivity Analyses Although quantitative pooling was circumvented, we conducted qualitative sensitivity analyses to determine the robustness of thematic conclusions. In particular, we analyzed whether shorter time points after injection always yielded shorter propagation distances, whether transgenic hosts showed greater tau spread than wild-type relatives, and whether seeds of mixed isoforms gave intermediate phenotypes. By describing differences between these subgroups, we could identify possible standardizations of protocols that would make future studies more comparable. These qualitative sensitivity checks were documented in supplementary tables. 2.10 Reporting Bias and Confidence in Evidence Statistical analysis using a funnel plot for publication bias was not possible with fewer than ten studies. We nevertheless screened each study's reported result against our registered protocol to assess selective reporting. A qualitative assessment of confidence in the evidence was made based on consistency between results from disparate groups, completeness of reporting, and likely effect of methodological limitation. In appreciation that GRADE methodology is specifically oriented toward clinical interventions, we avoided strict adherence to it; we provided a narrative assessment regarding the strength and trustworthiness of thematic inferences. 2.11 Ethical Considerations While our review encompassed no new experimentation on animals, we ensured all listed studies had institutional animal‑care and use approvals as reported. There has been no case where these claims were absent. 2.12 Data Availability and Transparency In line with open-science principles, we will also make our entire extraction database, systematic risk-of-bias tables, subgroup-analysis comments, and narrative synthesis tables available on the Open Science Framework (OSF). All these resources will have a distinct DOI and will be published under a Creative Commons Attribution (CC BY) license to facilitate independent verification and secondary analyses. 2.13 Theoretical Framing and Critical Engagement Our incorporation into the narrative was not just descriptive but actively engaged in current debates in tauopathy research. For instance, whether host genotype facilitates strain‑specific seeding is a controversial issue; comparing wild‑type and transgenic results, we attempted to provide illumination on this debate. Likewise, debate over whether mixed-isoform seeds more accurately mimic Alzheimer's pathology than primary 3R or 4R isolates was guided by our cross‐study comparisons of inclusion burden and propagation distance. The theoretically guided approach places our review at the forefront of harmonized, hypothesis‐driven preclinical tauopathy protocols, as a catalyst. 3. Results 3.1 Study Selection A systematic search of PubMed, Scopus, and Web of Science from Jan 2000 to May 2025 yielded 1437 records. After exclusion of 756 duplicates, 681 title and abstract level unique studies were screened. The vast majority, 673 studies, were excluded due to not reporting tau spreading in vivo, being conducted using non‑mammalian models, or involving other proteinopathies such as amyloidopathies. Of 11 full‑text articles screened, 3 were excluded: 2 studies were removed as they focused on endogenous tau rather than its exogenous counterpart, another 1 was removed because it was a review article rather than a primary study. A total of 8 studies fulfilled all inclusion criteria (Fig. 1). In total, four studies employed transgenic rodent hosts, three studies employed non‑transgenic models, and one study employed both types. 3.2 Study and Participants’ Characteristics 3.2.1 Inocula Biochemical Definition and Verification Before in vivo inferences can be drawn, inocula themselves must be described unambiguously. Pathological tau enrichment was achieved by research groups across the board with either sucrose gradient protocols ( 5 ) or sarkosyl-insoluble fractionation ( 12 , 16 ). While Boluda et al. employed a modified sucrose gradient to isolate paired helical filaments (PHFs) from CBD, AD, and DSAD donor brains, Ferrer et al. employed a detergent‑based extraction to resolve 3R‑ vs. 4R‑dominated species. In both cases, Coomassie-stained gels and Western blots utilizing a panel of phosphorylation‑independent (anti‑tau 17025) and phospho‑specific (PHF‑1, AT8) antibodies validated inoculum enrichment and disease specificity. Notably, non‑demented donor control preparations contained no detectable high‑molecular‑weight tau aggregates, reassuringly ruling out false positives upon host injection. Clavaguera et al. (2013) used a more whole-brain method to incubate total brain homogenates of six tauopathy subtypes (AD, TD, PiD, AGD, PSP, CBD) and subsequently treated them to silver staining (Gallyas‑Braak) and AT100 immunolabeling to verify "filamentous" tau seeding activity ( 7 ). Following up with serial propagation assays, they demonstrated that inocula from previously seeded mice with human P301S tau remained seeding competent and capable of causing secondary transmissions. Such activity reflects the self-sustaining character of the misfolded tau as in bona fide prion systems but distinguished by strain-dependent patterns ( 18 ). 3.2.2 Host Models and Injection Paradigms Selecting an appropriate host background is important when probing tau strain behavior. PS19 4R1N P301S human tau overexpressing transgenic mice were the primary model in Boluda et al. and Kaufman et al. In contrast, ALZ17 mice (longest human 4R tau) and non-transgenic C57BL/6 strains allowed Clavaguera and Narasimhan to bypass species barriers and the need for human tau overexpression. Ferrer and coworkers utilized hTau mice, overrepresenting 3R tau isoforms, thereby compensating for host splicing dynamics, whereas Hosokawa’s CRISPR-engineered Tau 3R/4R model more accurately reflected the endogenous human ratio. Finally, Ondrejcak utilized Lister Hooded rats, which allowed acute electrophysiological recordings by intracerebroventricular (ICV) injection, instead of stereotaxic hippocampal infusion. Injection sites varied as well but invariably included the hippocampus, overlying neocortex, or striatum; volumes were usually between 2.5 µl per site (Boluda) and 10 mg of tau strain in Kaufman’s high‑dose paradigm. Analysis time windows extended from one month post-injection in Boluda’s study to up to 15 months in Clavaguera’s ALZ17 work, introducing a longitudinal element to tau lesion propagation and maturation. The host-injection design matrix therefore constitutes an excellent paradigm for unraveling how early seeding events mature into mature pathology. 3.2.3 Tau Seeding Cell Type Specificity A recurring theme among such studies is that different tau strains have a preferential targeting of cellular populations. In PS19 mice, Boluda et al. (2015) observed CBD‑derived tau selectively inducing oligodendroglial inclusions, which at one month post-injection could be visualized in hippocampal fimbria (66% of animals) and subcortical white matter (50%) but were infrequent in neurons. By contrast, AD and DSAD tau preparations induced robust neuronal perikaryal pathology, AT8- and MC1‑positive pre‑tangles and NFT‑like deposits, within CA1, CA3, dentate gyrus, and more widely, with extensive spread through entorhinal cortex, locus coeruleus, and raphe nuclei ( 5 ). No oligodendroglial tau was seen at one month in AD‑tau-injected PS19 mice, which suggests that strain conformation, rather than injection trauma per se, dictates cellular tropism. Clavaguera's ALZ17 transgenics built on this narrative by showing that human astrocytic phenotypes, tufted astrocytes in PSP, astrocytic plaques in CBD, and typical AGD inclusions, were faithfully recapitulated, whereas PiD homogenates, although 3R tau containing, seeded fewer filamentous structures, possibly owing to a lack of concordance between the host’s 4R‑skewed tau expression and the 3R‑dominated seed ( 7 ). The fact that wild-type C57BL/6 mice also developed tau inclusions, though less frequently, suggests that endogenous murine tau can be incorporated into pathologic assemblies, obfuscating the species barrier in a quantitative sense. The detailed characteristics of the included studies, including inoculum source, host model, injection paradigm, and outcome measures, are summarized in Table 1. 3.3 Spatiotemporal Propagation Patterns In addition to cell type bias, anatomical patterns of tau dissemination are informative of underlying mechanisms. Clavaguera et al.'s data show that most tauopathies, once seeded, spread along neuroanatomical paths: hippocampal filaments spread to the optic tract, medial lemniscus, and amygdala six months after injection. Only PiD seeds were limited, perhaps due to the lack of available compatible tau isoforms in the host. Similarly, AD/DSAD tau in PS19 mice exhibited time- and dose-dependent spread in a connectome-congruent pattern, with contralateral hippocampal involvement by three to six months ( 5 ). These observations were extended by Narasimhan et al., who showed that injection site, hippocampus versus thalamus, determines the final anatomical spread of AT8-positive pathology, once more consistent with network connectivity, rather than strain identity, determining the topography of neurodegeneration at late stages ( 19 ). 3.5 Conformational and Biochemical Strain Features Strain‑specific conformers are not merely intellectual curiosities but have unique biochemical signatures. Kaufman et al. delineated 18 tau strains (DS2-DS19) and showed each has unique limited‑proteolysis digestion profiles and in vitro seeding kinetics. High split‑luciferase activity strains, such as: DS6, DS9, elicited general, fast‑spreading in vivo pathology, whereas low‑seeding strains (DS2, DS3, DS11, DS19) induced "rare seeding" localized phenotypes. Importantly, some strains elicited astrocytic plaque deposition or rod‑shaped microglial activation, previously thought to be human subtype‑exclusive pathologies, mandating that conformational subtleties encode cell type tropism ( 18 ). Ferrer et al. added a new twist to explain that homogenates from what seemed to be 4R tauopathies (GGT) could seed 3R tau deposition in hTau mice, and vice versa, that host splicing machinery was hijacked by arriving seeds to modulate exon 10 inclusion. This control of splicing could have a dramatic impact on cytoskeletal stability and synaptic function, and demonstrates that tauopathy models will now need to consider dynamic host-seed interactions, not mere static isoform complements. 3.6 Neurodegeneration, Gliosis, and Functional Outcomes It would be easy to consider tau seeding a passive histopathological curiosity, but several studies associated aggregation with neuron loss, gliosis, and synaptic dysfunction. Boluda et al. observed time-dependent CA3 neuron loss in PS19 mice injected with AD/DSAD-tau but did not observe overt cell death following CBD-tau injections despite clear oligodendroglial pathology. Narasimhan et al. observed that PSP-tau induced much more AT8 inclusions and astrocytic tau transmission in non-Tg mice than AD or CBD seeds, possibly anticipating increased neurotoxicity. Microglial activation patterns were also varied: some Kaufman strains induced rod-shaped microglia in the ipsilateral hippocampus, but others made microglia quite inactive, implying that tau conformation determines the involvement of the innate immune system. In a related field, Ondrejcak et al. demonstrated that acute inhibition of hippocampal long-term potentiation in rats was caused by aqueous extracts of AD and PiD brains, that this dysfunction in synaptic function was reversible by immunodepletion of either Aβ or tau, and that chronic LTP dysfunction, assayed two to four weeks later, had concomitant immunodepletion profiles, which suggested that diffusible tau species, perhaps oligomeric rather than fibrillar, chronically exert synaptotoxicity. Of interest, with co-injection of subthreshold volumes of several different AD extracts, their combined effects were adequate for deranging plasticity, suggesting synergistic interaction of tau and Aβ, an interaction still contentious but of self-evident significance to Alzheimer’s disease pathogenesis. 3.7 Amyloid-binding and maturation properties The structure of tau aggregates also varies between strains. MC1 and TG3 immunoreactivities, pathological conformation markers, emerge early in AD/DSAD-tau injections, with thioflavin-S positivity for β-sheet-enriched fibrillar inclusions. CBD-tau aggregates are MC1-positive but thioflavin-negative even after six months, consistent with human CBD pathology where oligodendroglial coiled bodies are non-amyloidogenic ( 5 ). Taniguchi et al. (2024) extended these results by using an anti-N368 antibody to map C-terminal tau fragments, demonstrating that astrocytic plaques in CBD are non-N368 immunoreactive, while tufted astrocytes in PSP are intensely N368-positive ( 20 ). Such proteolytic fingerprints also demonstrate that disease-defining fibril folds not only specify aggregation but also protease susceptibility and immune recognition. 3.8 Serial Propagation and Model Refinement Clavaguera et al. offered the most compelling evidence that tau seeds can be serially propagated. Homogenates from previously inoculated ALZ17 mice carrying human P301S tau, upon re-inoculation into naive hosts of either ALZ17 or C57BL/6, communicated neuronal and oligodendroglial disease with conservation of defining features, such as coiled bodies and neuropil threads. This serial passage is prion-like and promises high-throughput strain definition, subject to the caveat that passage through the murine host might entail adaptation artifacts of no concern for human disease progression. 3.9 Risk-of-Bias When assessed for risk of bias through the SYRCLE risk of bias tool, we observed that the included studies were generally mixed in many domains, with several domains frequently rated as unclear. The overall ratings are summarized in Table 2, while domain‑level details are provided in Supplementary Appendix B. Taniguchi et al. (2024), Narasimhan et al. (2017) were found to have high risk of bias related to sequence generation, allocation concealment, and outcome assessment. On the other hand, the risk of bias related to baseline characteristics was at a low risk across all studies. The studies conducted by Hosokawa et al. (2022), Clavaguera et al. (2013), Ferrer et al. (2022), and Ondrejcak et al. (2023) primarily had unclear risk of bias across domains related to randomization, housing, and blinding domains. However, they were at a low risk of bias for incomplete outcome data. Kaufman et al. (2016) had a high risk of bias in baseline characteristics. On the other hand, the risk of bias for outcome assessment and reporting was low. For the study conducted by Boluda et al. (2015), the risk of bias was low across several domains. In contrast, Boluda et al. (2015) had a high risk of bias for post‑injection housing. Overall, selective outcome reporting was generally low risk, and incomplete outcome data were well managed across most studies. 4. Discussion 4.1 Summary of Main Findings This systematic review of eight head-to-head comparative studies highlights the prion-like behavior of tau strains in rodent models, shedding light on how primary tauopathies, those predominated by 3R or 4R tau isoforms, and secondary tauopathies, those with mixed 3R/4R compositions, differentially spread pathology in vivo. Across various sites of inoculation, such as hippocampus, cortex, striatum, and thalamus, and observation intervals between 1 to 15 months, a clear picture reveals itself: human brain-derived tau seeds not just induce aggregation but also preserve isoform-specific as well as cell-type tropisms characteristic of their originating diseases. For example, seeds of primary 4R tauopathies such as corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) almost exclusively target glial cells, producing astrocytic plaques as well as oligodendroglial coiled bodies, whereas seeds with mixed 3R/4R isoforms from Alzheimer's disease (AD) preferentially promote neuronal neurofibrillary tangles (NFTs) with associated neurotoxicity, including extensive CA3 neuron loss in models such as PS19 transgenic mice ( 5 , 19 ). Such effects were robust, transcending host genotypes, varying between tau overexpressing transgenics to CRISPR-engineered humanized models, and injection paradigms, emphasizing a priori conformational dictate of a seed over a composition of isoforms of pathology, cell preference, as well as anatomical spread over neuroanatomical pathways as opposed to diffusion per se. Notably, this review emphasizes the heritable nature of tau strains, as seen with studies of serial propagation experiments in which induced pathologies preserved disease-specific characteristics upon transmission to naïve hosts ( 7 ). Biochemical signatures, including differential protease resistances at residue N368 and amyloid-binding capabilities, further validate conformational fidelity ( 5 , 20 ). Functional endpoints, albeit less uniformly assessed, link certain strains to synaptic dysfunction and gliosis, with AD extracts suppressing long-term potentiation in rat models, a reversible effect by removal of tau or Aβ by immunodepletion, indicating both Aβ- and tau-mediated synergistic interactions in mixed pathologies ( 21 ). Overall, these results argue in favor of a form of a priori protective barrier between isoforms, such that primary strains having a predilection for a glial tropism, with secondary ones having a neuronal predominance. While no overt meta-analysis was possible owing to methodological variety, narrative synthesis identifies high consistency for strain-specific behavior, albeit moderate certainty owing to a priori non-human origin of this body of evidence. This synthesis refines earlier conceptualizations of tau as a prionoid protein and extends the concept by demonstrating a role for isoform barriers, as well as host-seed dynamics in a living state in vivo ( 3 , 18 ). 4.2 Interpretation of the findings Across the head-to-head in vivo comparisons included in this review, the most defensible interpretation is that tau seed conformation is the primary determinant of downstream pathology, while the host environment (isoform availability, genotype, and connectivity) governs the degree and pattern of recruitment. Primary, isoform-dominant seeds (3R or 4R) consistently reproduce cell-type tropisms characteristic of their human diseases (glial predominance for many 4R seeds; neuronal predominance for mixed AD seeds), and serial passage preserves these defining features, supporting a heritable, strain-encoded signal rather than a stochastic aggregation process. The directional results (strain → cell-type preference; strain + host → anatomical spreading) agree across various host backgrounds and sites of injections, revealing reproducible biological signals. Effect sizes and time courses, on the other hand, vary with host genotype, extraction technique, and post-inoculation time interval, so a high consistency exists for direction but moderate one is present for magnitude and temporal dynamics. It is a pattern that permits us to deal with the seeding hypothesis as a mechanistic model that, in principle, reproducible yet is experimentally context sensitive. Structural and biochemical fingerprints (distinct protease resistance, C-terminal fragments, amyloid-binding properties) provide a plausible molecular basis for tropism: specific fibril folds likely determine cellular uptake, recruitment kinetics, and proteostatic handling by neurons versus glia. Host responses appear to act as amplifiers or brakes on seeding. Together these lines of evidence support a bidirectional model: seeds template conformation, and the host cell milieu, isoform repertoire, proteases, and immune state, transforms that template into the observed anatomical and functional phenotype. This synthesis DOES NOT claim that propagation in rodents exactly reproduces human disease timelines, clinical phenotypes, or full comorbidity interactions, nor does it claim that all experimental seed preparations are interchangeable. It rather defines a reproducible mechanistic correlate (strain-specific templating modulated by host factors) and delimits uncertainties (magnitude, timing, and clinical generalizability). In controlled in vivo comparisons, evidence holds that tauopathies are best conceptualized as strain-driven disorders where phenotypic variability arises as a product of the interactions between host biology and seed conformation. 4.3 Comparison With Previous Evidence Our findings resonate with the growing body of literature on tau propagation, specifically in emphasizing the prion-like hypothesis originally explained in studies that described the templated misfolding and subsequent cell-transmissive tau aggregates ( 7 , 22 ). Earlier research on other strains with synthetic preformed fibrils (PFFs), for instance, did establish strain-like diversity but in an in vitro setting, or using artificially modeled aggregates that would be insensitive to the heterogeneity in seed-derived samples from human sources ( 13 , 14 ). By reviewing head-to-head analyses comparisons patient brain-derived inocula, however, the present review constructs more in vivo evidence for seed-based propagation from CBD or PSP with more direct in vivo similarity in that these seeds do actually induce pathologic gliosis in a manner that parallels human tauopathies where 4R tau is the only species predominantly found in glial inclusions ( 23 , 24 ). There is consistency with Wenger et al. (2023), who documented symptomatic progression in tauopathy models following aggregate injection, to which our review would highlight isoform-specific limitations in 4R-dominant hosts using PiD (3R type), a phenomenon less emphasized in prior overviews that focused on AD-centric mixed tau ( 25 , 26 ). Discrepancies with previous reviews arise in the context of host modulation. For example, while Robert et al. (2021) reported strain-specific propagation in human tau models, they did not systematically compare primary versus secondary strains, potentially underestimating the role of glial tropism seen here in non-transgenic mice ( 19 ). Similarly, Jang et al. (2024) demonstrated seeding in genetically modified mice expressing human tau, aligning with our observations of enhanced 3R propagation in humanized environments like hTau or CRISPR models ( 12 , 16 ). However, differences in study dates and designs, earlier works like Clavaguera et al. (2014) using peripheral administration to trigger central tauopathy, suggest that central inoculations in our included studies may accelerate pathology but compress timelines, potentially exaggerating spread compared to slower, endogenous progression in human diseases ( 6 , 11 ). However, theoretical discrepancies remain with respect to the “prion-like” label. While our findings verify self-propagation and heritability (Kaufman et al., 2016), they refute homogeneous models by incorporating the role of splicing shifts induced by seeds (Ferrer et al., 2022), which have historically been overlooked in favor of conformational determinism alone ( 10 , 27 ). Instead, it aligns with the more recent findings in in the cryo-EM studies, validating different filament structures in AD versus CBD, accounting for differences in protease sensitivity ( 13 , 14 ), yet our review incorporated more in vivo evidence on behavioral differences, like microglial activation patterns varying by strain ( 18 ). Compared to guidelines from neuropathological societies, which classify tauopathies on the basis of inclusion morphology ( 24 ), it appears from the scope of our interest and the findings of this review that inoculation models could refine diagnostics by predicting strain behaviors, though discrepancies with synthetic fibrils ( 28 ) indicate human-derived seeds offer superior fidelity. Ultimately, these comparisons support a shift in the conversation from mere aggregation to strain-host interplay, resolving some debates on tau’s pathogenicity while opening others on translational applicability. 4.4 Mechanistic Insights Mechanistically, these findings reveal that tau strain conformations encode cellular tropism through structural elements that direct cellular uptake, recruitment, and maturation. By biological plausibility, establish prions paradigms where quaternary folds encode host interaction ( 3 ), with CBD’s legumain resistance at N368 preserves non-amyloid glial inclusions aggregates versus AD’s cleavage susceptibility yields amyloid-positive NFTs ( 20 ). Host factors mediate these processes through splicing feedback, potentially by PiD’s upregulation of 3R gene expression, enhancing self-propagation ( 12 ), a mechanism also suggested in aberrant in human tauopathies' alternative splicing dysregulation ( 22 ). Neuroinflammatory responses, suggested from the strain-varying microglial morphologies, could also mediate shape vulnerability, although underexplored investigated within these studies ( 18 ). Synergies with co-pathologies, such as Aβ-tau interactions perturbing and disrupting LTP function, instead imply convergent pathophysiological mechanisms in secondary (mixed) tauopathies ( 21 ), inline with hypotheses of oligomeric tau’s synaptotoxicity ( 25 ). Altogether, these perspectives suggest a bidirectional model, in which seeds template pathology, with the host then refining it through proteostasis and connectivity, explaining clinical diversity beyond simple diffusion. 4.5 Heterogeneity Heterogeneity among the studies reviewed, due to differences in seed preparations, models of inoculation, and read-outs, is likely to affect the observed outcomes but does not detract from the core strain-specific patterns. Of course, overexpression of tau in the PS19 mouse background could amplify pathology burdens, lowering seeding thresholds and potentially inflating glial involvement in CBD injections compared to physiological expression in CRISPR models ( 5 , 16 ). Between-population differences, such as species-specific isoform ratios (murine 4R-dominant models limit 3R PiD propagation), also play a role, together with intervention durations (up to 15-month observation), where mature spreading along connectomes is apparent ( 7 , 19 ). All these also resonate with the issue in tauopathy research in general, where reproducibility is affected by research methodologies ( 1 , 9 ). 4.6 Strengths and Limitations Strengths in this review arise in its focus on head-to-head study designs, so direct comparisons for strains can be made while avoiding confounding factors, an improvement over more general tauopathy reviews (Kovacs, 2015). The extensive database search combined with the various rodent models is key for preclinical setting generalizability, with narrative syntheses accommodating any heterogeneity, allowing for a complex understanding regarding prion-like fidelity ( 3 ). Also, one of the key strengths in our review is that it included studies that utilized appropriate biochemical validation tests that improve the quality of evidence by potentially avoiding artifactual seedings ( 7 , 12 ). However, these findings are also subject to some limitations, with only eight studies included (n = 8), and the lack of meta-analyses and formal bias assessments like funnel plots. However, methodological heterogeneity, the varied extractions, genotypes, and timelines, makes the cross-study synthesis subject to discrepancies among the studies, such as the propagation efficiencies ( 15 ). Our English-language restriction and exclusion of synthetic PFFs introduced publication and scope biases ( 27 ). The certainty of our findings is limited by weaknesses in the methodology of the included studies. Several domains, particularly randomization, blinding, and housing, were frequently rated as unclear or high risk, which may have inflated observed effects. Nevertheless, outcome reporting and handling of incomplete data were generally low risk, lending some confidence to the overall trends. Other study-level limitations include: small sample sizes, and reliance on rodent models that may not capture human comorbidities or aging ( 2 ). 4.8 Clinical, Policy, and Theoretical Implications Clinically, these findings prove that targeting conformers, strain-specific, could be a force of change in tauopathies therapies, such as isoform-selective antibody approaches to stop glial versus neuronal transmission in primary versus secondary diseases ( 13 , 22 ). In AD, therapies for mixed tau could target synaptic protectors, with CBD/PSP targeting glial modulators, guiding precision therapies in tandem with prion disease approaches ( 3 ). Policy makers could then advocate for standardized in vitro protocols to expedite translation efforts, possibly impacting funding and budgeting priorities for more accurate and efficient humanized models ( 16 ). Theoretically, our findings pose a challenge to reductionist models of understanding tau as a uniform homogeneous protein, and extending into the larger proteinopathies conversation where the interactivity between the host and strain is correlational in terms of heterogeneity, closing the gap with synucleinopathies versus amyloids ( 24 , 25 ). Net benefits for strain identification outweigh any possible harm in artifact variance in rodent models interpreted in human trials ( 10 , 27 ). 4.9 Future Research Directions Future investigations should instead emphasize protocol standardization, especially standardized seed characterization through cryo-EM, proteomics for meta-analyzing ( 13 , 14 ), more complex models incorporating aging factors and comorbidity, such as, Aβ and tau ( 21 ). Longitudinal studies using multimodal endpoints for imaging, behavioral, and electrophysiological measurements could attempt correlations between propagation events and their contribution to cognitive and functional outcomes ( 9 ). Mechanistic studies into glial cell-based propagation strategies could identify treatment approaches, while comparing aggregate differences between humans and animals using direct comparison protocols in cryo-EM would validate ( 20 ). 5. Conclusion Evidence from the present systematic review supports the notion that tau seeds derived from primary (3R- or 4R-dominant) and secondary (mixed 3R/4R) tauopathies of humans preserve their isoform- and cell type-specific pathologies in rodent models in a manner where glial cell tropism is a characteristic feature in principle for strains derived from corticobasal degeneration and progressive supranuclear palsy tauopathies, with neuronal preference for neurofibrillary tangles in Alzheimer’s disease-derived strains. The phenotypic diversity in these strains is thus reflected in their adaptability to their states as either seed-cores or mimetic molecules in their surroundings. The certainty of evidence is only moderate, with heterogeneity in research methodology across the eight studies making direct comparison unfeasible for meta-analysis, potentially leading to uneven comparison factors. Additionally, its non-human preclinical focus limits direct applicability to humans, where age-related comorbidities and complex co-pathologies like amyloid-β interactions are commonplace, potentially underestimating translational challenges. Also, within-study factors in the original research, particularly in studies with smaller sample sizes, affect these certainties somewhat, even with head comparison studies. At a clinical level, these findings argue for the need for strain-specific diagnostics and treatment strategies; neurologists could initially target glial cells in primary tauopathies versus synaptic protectors in secondary tauopathies. Policymakers should support higher research budgets for more reproducible protocols in animal models to collectively mitigate the currently unbeatable nature of tauopathies, as discussed in more general analyses. Researchers should combine these models with human data to produce more informed predictions rather than rely on the rapidly accelerated timelines that may not accurately represent disease in humans. Declarations Funding Declaration This research did not receive any specific grant from funding agencies in the public, commercial, or not‑for‑profit sectors. • Clinical Trial Number : not applicable. • Consent to Publish Declaration : not applicable. • Consent to Participate Declaration : not applicable. Author Contribution M.A.W. and A.K.B. conceived the study design and wrote the main manuscript text.M.S. and A.T. performed the systematic search and data extraction.A.H. and A.Y.E. conducted risk‑of‑bias assessment and prepared summary tables.A.H.A. and A.G.E. synthesized results and drafted the discussion section.M.E. and A.E. prepared figures and formatted references.All authors (M.A.W., A.K.B., M.S., A.T., A.H., A.Y.E., A.H.A., A.G.E., M.E., A.E.) reviewed the manuscript and approved the final version. Data Availability In line with open-science principles, we will also make our entire extraction database, systematic risk-of-bias tables, subgroup-analysis comments, and narrative synthesis tables available on the Open Science Framework (OSF). All these resources will have a distinct DOI and will be published under a Creative Commons Attribution (CC BY) license to facilitate independent verification and secondary analyses. 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Tau and amyloid β protein in patient-derived aqueous brain extracts disrupt synaptic plasticity independently and converge in inhibiting mitochondrial bioenergetics. J Neurosci. 2023;43(32):5870–85. Kaur P, Khera A, Alajangi HK. Role of Tau in Various Tauopathies and Emerging Therapies. Mol Neurobiol. 2023;60:1690–720. Kovacs GG. Invited review: Neuropathology of tauopathies: a practical approach. Neuropathol Appl Neurobiol. 2015;41(1):1–14. Zhang X, Wang J, Zhang Z, Ye K. Tau in Neurodegenerative Diseases: Molecular Mechanisms and Classification. Transl Neurodegener. 2024;13:40. Nath S, Agholme L, Kurudenkandy FR, Granseth B, Marcusson J, Hallbeck M. Spreading of neurodegenerative tau protein in the brain. J Intern Med. 2012;271(6):518–25. Wenger K, Viode A, Schlaffner CN. Common Mouse Models of Tauopathy Reflect Early but Not Late Human Disease. Mol Neurodegener. 2023;18:10. Mietelska-Szadkowska K. Tau protein and tauopathies. I. Function and structure of tau protein. Folia Neuropathol. 2020;58(2):87–98. Sharma AM, Saiardi A. Recombinant tau protein aggregates: preparation and use. Methods Mol Biol. 2022;2521:235–48. Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files PRISMAflowdiagram.docx RiskofBias.xlsx Table 2 SearchStrategy.docx StudyCharacteristics.xlsx Table 1 ProsperoProtocol.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8090222","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":550550799,"identity":"ab07e0a5-edd8-491a-ae2a-5acdf7da9ea0","order_by":0,"name":"Mohamed A. 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Introduction","content":"\u003cp\u003eTau, a microtubule-associated protein, is of crucial significance to neuronal axons as it stabilizes microtubular networks necessary for intracellular transport and cytoskeletal stability (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Alternative splicing of the MAPT gene produces six isoforms in the adult human central nervous system that differ primarily in the presence of three (3R) or four (4R) microtubule-binding repeat domains (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Pathologically, abnormal post-translational modifications, hyperphosphorylation, induce the dissociation of tau from microtubules. It aggregates to form insoluble paired helical filaments (PHFs), which further mature to neurofibrillary tangles (NFTs) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). NFTs are a pathognomonic neuropathological lesion in tauopathies, a family of heterogeneous neurodegenerative diseases that are defined by progressive neuronal dysfunction and regional brain atrophy (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eTauopathies are classified based on the dominant tau isoform found in the inclusions. Primary tauopathies have predominantly 3R or 4R tau deposits, while secondary tauopathies have mixed 3R/4R pathology (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), for example, are primary 4R tauopathies with widespread glial pathology, including astrocytic plaques and oligodendroglial coiled bodies (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Pick\u0026rsquo;s disease (PiD), by contrast, has predominant 3R tau deposition (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Alzheimer\u0026rsquo;s disease (AD), the most common secondary tauopathy, has mixed 3R/4R pathology mainly in neuronal NFTs (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Beyond isoform ratios, these clinicopathological distinctions involve cell-type-specific susceptibility, inclusion morphologies, and biochemical mixtures. As a further point, C-terminal tau fragments truncated at residue N368 are found consistently in AD and PSP but not in CBD, suggesting that these fragments may reflect more basic strain differences involving conformation-dependent proteolytic cleavage (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThese observations serve as the foundation of the tau strain hypothesis, in which structurally different aggregate conformations (\"strains\") determine regional tropism, cell susceptibility, and patterns of spread (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Templated misfolding is the basis of prion-like trans-synaptic transmission, in which disease-causing tau seeds recruit endogenous tau into enlarging aggregates (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In vitro patient extract or synthetic preformed fibril (PFF) assays demonstrate strain-dependent aggregation kinetics within cell models (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In vivo assays demonstrate distinct pathologies as well: intracerebral inoculation of CBD-derived tau in transgenic mice seeds oligodendroglial inclusions preferentially, whereas AD-tau seeds seed neuronal aggregates (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Genome-edited models expressing endogenous human-like 3R/4R tau ratios also exhibit isoform-specific recruitment, in which PiD seeds spread 3R pathology selectively (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Non-transgenic models validate human strain tropism, in which PSP-tau inoculation selectively causes astroglial pathology in the absence of AD-tau exposed animals (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eDespite these developments, significant methodological constraints exclude direct comparisons between human brain-derived and laboratory-derived strains (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Different models or isolation procedures are applied in the majority of studies, and these can suppress native strain properties (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Recombinant 4R fibrils, for instance, do not recapitulate robust gliotropism of native CBD-derived strains in PS19 mice (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) Moreover, regional spreading pattern differences between natural and amplified strains show that procedural artifacts can perturb pathogenic pathways (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Therefore, whether synthesized or amplified strains truly represent the neuropathological and biochemical properties of their human-derived counterparts is contentious (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThis systematic review will seek to clarify these uncertainties by a rigorous meta-analysis of head-to-head contrasts in isogenic models. We anticipate primary seeds to exhibit greater fidelity towards simulating human glial tropism and isoform-selective recruitment, and secondary strains to exhibit attenuated or aberrant propagation dynamics as a consequence of purification or amplification artefacts. By evidence synthesis across harmonized experimental paradigms, this project seeks to clarify strain-specific pathomechanisms and optimize translational strategies against tau propagation.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Registration and Reporting Standards for the Protocol\u003c/h2\u003e\u003cp\u003eWe pre‑registered our systematic review protocol on PROSPERO (CRD420251053445) on 24 June 2025 after a preliminary scoping search confirmed that no duplicate reviews were underway. The protocol was developed in line with the SWiM (Synthesis Without Meta‑analysis) reporting guidance, which provides structured recommendations for transparently conducting and presenting the narrative syntheses (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). This framework informed the specification of grouping strategies, synthesis methods, and approaches to reporting heterogeneity. Any amendments to the registered protocol were documented in PROSPERO with corresponding dates and justifications.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Information Sources and Search Dates\u003c/h2\u003e\u003cp\u003eSystematic electronic literature searching was performed in these three databases: MEDLINE (via PubMed), Scopus, and Web of Science back to the start of each database through 4 May 2025, when searches were most recently up to date. To identify research from non-standard publication sources, we did not hand‑search reference lists from included articles or similar reviews, conference proceedings, and clinical‑trial registries and the databases for pertinent dissertations or technical reports. All of the references were imported into JabRef for auto‑deduplication; this was then manually verified to ensure that near duplicate records or alternative spellings weren't mistakenly eliminated.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Search Strategy\u003c/h2\u003e\u003cp\u003eStriking a balance between sensitivity and specificity, we used controlled vocabulary together with free‑text terms. The central search strategy within PubMed was:\u003c/p\u003e\u003cp\u003e(\"tau\") AND (\"aggregation\" OR \"propagation\") AND (\"injections\" OR \"seeding\" OR \"inoculation\") AND (\"animal models\" OR \"mouse\" OR \"rat\")\u003c/p\u003e\u003cp\u003eWe adapted this search to Scopus and Web of Science, applying validated animal‑study filters and restricting to English‑language, peer‑reviewed journal papers. Complete search strings, including database‑specific syntax and any applied limits, are provided in Supplementary Appendix A.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Inclusion Criteria\u003c/h2\u003e\u003cp\u003eStudies were included if they met all of the following:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eAnimal Model\u003c/b\u003e: Employed wild‑type or tau transgenic mice (e.g., C57BL/6, PS19, 6hTau).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eIntervention\u003c/b\u003e: Performed stereotactic intracerebral injections of human brain‑derived tau aggregates.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003ePrimary seeds\u003c/b\u003e were Pick's disease tissue (3R‑tau) and 4R‑tauopathies (PSP, CBD, GGT).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eSecondary seeds\u003c/b\u003e were Alzheimer's disease tissue with mixed 3R\u0026thinsp;+\u0026thinsp;4R tau.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eComparative Design\u003c/b\u003e: Performed within‑study, head‑to‑head comparisons of primary vs secondary seeds under matched inoculation protocols and post‑injection intervals.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eOutcomes\u003c/b\u003e: Reported quantitative estimates of tau inclusion burden (percent immunopositive area or counts/mm\u0026sup2;) and propagation distance (mm). Secondary outcome measures included 3R/4R isoform ratio and regional neuroanatomic distribution.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003ePublication\u003c/b\u003e: Reported in full-text, peer-reviewed English language publications.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eExclusion criteria included in vitro or human-only research, non-comparative investigations without quantitative head-to-head comparisons, task-based paradigms, conference abstracts, posters, and review articles.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Study Selection\u003c/h2\u003e\u003cp\u003eFollowing deduplication, titles and abstracts were imported into Rayyan QCRI for blinded title/abstract screening by two distinct reviewers. Disagreements, approximately 13 percent of decisions, were resolved and, if not, adjudicated by a third reviewer. Full texts of studies of potential eligibility were screened against the criteria listed above. A PRISMA flow diagram (Fig.\u0026nbsp;1 in the Appendix) shows the records screened, assessed for eligibility, and included, and reason for exclusion at each stage.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6 Data Extraction and Management\u003c/h2\u003e\u003cp\u003eWe created a structured extraction form in Microsoft Excel, based on Cochrane recommendations and adjusted through pilot exercise on four randomly chosen studies. The following variables were extracted:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eAnimal Characteristics\u003c/b\u003e: Species, strain, sex distribution, age at inoculation, housing conditions.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eInoculum Information\u003c/b\u003e: Source of Tauopathy, isoform composition, methods of extraction and purification, dosage and volume, coordinates of injection, and delivery device.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eTiming of Experiment\u003c/b\u003e: Post-injection time points (days) and intermediate measures.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eImmunostaining Procedures\u003c/b\u003e: Antibody clones, dilutions, antigen retrieval procedures, and threshold criteria.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eQuantitative Outputs\u003c/b\u003e: Inclusion burden measures, extents of spread, 3R/4R ratio, and any accompanying behavioral or biochemical correlates.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eStudy-Level Covariates\u003c/b\u003e: Sources of funding, conflict-of-interest statements, ethical approval statements.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eTwo reviewers independently performed data extraction; disagreements were resolved by consensus or, as a last resort, by referral to a third member of staff.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e2.7 Risk of Bias and Quality Assessment\u003c/h2\u003e\u003cp\u003eAs the preclinical, animal-study setting, methodological quality was assessed with SYRCLE's risk-of-bias tool for selection, performance, detection, attrition, reporting, and other biases. Two authors independently assessed each domain without knowledge of authorship and journal titles. Disagreements were resolved by consensus or by sending the dispute to a third reviewer. Total risk-of‐bias ratings are presented in Table\u0026nbsp;2, and raw scores in Supplementary Appendix B.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e2.8 Data Synthesis and Thematic Framework\u003c/h2\u003e\u003cp\u003eSubstantial heterogeneity between host genotypes, inoculation regimens, outcome measures, and reporting conventions precluded a formal meta-analysis. Instead, we conducted a thematic narrative synthesis, basing our approach on theoretical models of prion‐like tau propagation, network‐based susceptibility, and isoform‐specific seeding kinetics. Studies were stratified along three main axes: (I) \u003cb\u003eSeed Isoform\u003c/b\u003e: 3R vs. 4R vs. mixed 3R\u0026thinsp;+\u0026thinsp;4R, (II) \u003cb\u003eHost Genotype\u003c/b\u003e: Wild-type vs. transgenic, and (III) \u003cb\u003eTiming\u003c/b\u003e: Short (\u0026lt;\u0026thinsp;30 days) vs. long (\u0026ge;\u0026thinsp;30 days) post-injection intervals.\u003c/p\u003e\u003cp\u003eWe tabulated study characteristics and outcomes within each stratum to facilitate cross‑study comparison. Within each stratum, we summarized results to identify trends in seeding efficiency, regional tropism, and recruitment of isoforms. Where two or more studies reported the same finding, we qualitatively compared effect sizes and placed findings within context of methodological difference, such as: thresholding criteria for immunostaining or anatomical definitions of propagation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e2.9 Subgroup and Sensitivity Analyses\u003c/h2\u003e\u003cp\u003eAlthough quantitative pooling was circumvented, we conducted qualitative sensitivity analyses to determine the robustness of thematic conclusions. In particular, we analyzed whether shorter time points after injection always yielded shorter propagation distances, whether transgenic hosts showed greater tau spread than wild-type relatives, and whether seeds of mixed isoforms gave intermediate phenotypes. By describing differences between these subgroups, we could identify possible standardizations of protocols that would make future studies more comparable. These qualitative sensitivity checks were documented in supplementary tables.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e2.10 Reporting Bias and Confidence in Evidence\u003c/h2\u003e\u003cp\u003eStatistical analysis using a funnel plot for publication bias was not possible with fewer than ten studies. We nevertheless screened each study's reported result against our registered protocol to assess selective reporting. A qualitative assessment of confidence in the evidence was made based on consistency between results from disparate groups, completeness of reporting, and likely effect of methodological limitation. In appreciation that GRADE methodology is specifically oriented toward clinical interventions, we avoided strict adherence to it; we provided a narrative assessment regarding the strength and trustworthiness of thematic inferences.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e2.11 Ethical Considerations\u003c/h2\u003e\u003cp\u003eWhile our review encompassed no new experimentation on animals, we ensured all listed studies had institutional animal‑care and use approvals as reported. There has been no case where these claims were absent.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e2.12 Data Availability and Transparency\u003c/h2\u003e\u003cp\u003eIn line with open-science principles, we will also make our entire extraction database, systematic risk-of-bias tables, subgroup-analysis comments, and narrative synthesis tables available on the Open Science Framework (OSF). All these resources will have a distinct DOI and will be published under a Creative Commons Attribution (CC BY) license to facilitate independent verification and secondary analyses.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e2.13 Theoretical Framing and Critical Engagement\u003c/h2\u003e\u003cp\u003eOur incorporation into the narrative was not just descriptive but actively engaged in current debates in tauopathy research. For instance, whether host genotype facilitates strain‑specific seeding is a controversial issue; comparing wild‑type and transgenic results, we attempted to provide illumination on this debate. Likewise, debate over whether mixed-isoform seeds more accurately mimic Alzheimer's pathology than primary 3R or 4R isolates was guided by our cross‐study comparisons of inclusion burden and propagation distance. The theoretically guided approach places our review at the forefront of harmonized, hypothesis‐driven preclinical tauopathy protocols, as a catalyst.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Study Selection\u003c/h2\u003e\u003cp\u003eA systematic search of PubMed, Scopus, and Web of Science from Jan 2000 to May 2025 yielded 1437 records. After exclusion of 756 duplicates, 681 title and abstract level unique studies were screened. The vast majority, 673 studies, were excluded due to not reporting tau spreading in vivo, being conducted using non‑mammalian models, or involving other proteinopathies such as amyloidopathies. Of 11 full‑text articles screened, 3 were excluded: 2 studies were removed as they focused on endogenous tau rather than its exogenous counterpart, another 1 was removed because it was a review article rather than a primary study. A total of 8 studies fulfilled all inclusion criteria (Fig.\u0026nbsp;1). In total, four studies employed transgenic rodent hosts, three studies employed non‑transgenic models, and one study employed both types.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Study and Participants\u0026rsquo; Characteristics\u003c/h2\u003e\u003cdiv id=\"Sec19\" class=\"Section3\"\u003e\u003ch2\u003e3.2.1 Inocula Biochemical Definition and Verification\u003c/h2\u003e\u003cp\u003eBefore in vivo inferences can be drawn, inocula themselves must be described unambiguously. Pathological tau enrichment was achieved by research groups across the board with either sucrose gradient protocols (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) or sarkosyl-insoluble fractionation (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). While Boluda et al. employed a modified sucrose gradient to isolate paired helical filaments (PHFs) from CBD, AD, and DSAD donor brains, Ferrer et al. employed a detergent‑based extraction to resolve 3R‑ vs. 4R‑dominated species. In both cases, Coomassie-stained gels and Western blots utilizing a panel of phosphorylation‑independent (anti‑tau 17025) and phospho‑specific (PHF‑1, AT8) antibodies validated inoculum enrichment and disease specificity. Notably, non‑demented donor control preparations contained no detectable high‑molecular‑weight tau aggregates, reassuringly ruling out false positives upon host injection.\u003c/p\u003e\u003cp\u003eClavaguera et al. (2013) used a more whole-brain method to incubate total brain homogenates of six tauopathy subtypes (AD, TD, PiD, AGD, PSP, CBD) and subsequently treated them to silver staining (Gallyas‑Braak) and AT100 immunolabeling to verify \"filamentous\" tau seeding activity (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Following up with serial propagation assays, they demonstrated that inocula from previously seeded mice with human P301S tau remained seeding competent and capable of causing secondary transmissions. Such activity reflects the self-sustaining character of the misfolded tau as in bona fide prion systems but distinguished by strain-dependent patterns (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section3\"\u003e\u003ch2\u003e3.2.2 Host Models and Injection Paradigms\u003c/h2\u003e\u003cp\u003eSelecting an appropriate host background is important when probing tau strain behavior. PS19 4R1N P301S human tau overexpressing transgenic mice were the primary model in Boluda et al. and Kaufman et al. In contrast, ALZ17 mice (longest human 4R tau) and non-transgenic C57BL/6 strains allowed Clavaguera and Narasimhan to bypass species barriers and the need for human tau overexpression. Ferrer and coworkers utilized hTau mice, overrepresenting 3R tau isoforms, thereby compensating for host splicing dynamics, whereas Hosokawa\u0026rsquo;s CRISPR-engineered Tau 3R/4R model more accurately reflected the endogenous human ratio. Finally, Ondrejcak utilized Lister Hooded rats, which allowed acute electrophysiological recordings by intracerebroventricular (ICV) injection, instead of stereotaxic hippocampal infusion.\u003c/p\u003e\u003cp\u003eInjection sites varied as well but invariably included the hippocampus, overlying neocortex, or striatum; volumes were usually between 2.5 \u0026micro;l per site (Boluda) and 10 mg of tau strain in Kaufman\u0026rsquo;s high‑dose paradigm. Analysis time windows extended from one month post-injection in Boluda\u0026rsquo;s study to up to 15 months in Clavaguera\u0026rsquo;s ALZ17 work, introducing a longitudinal element to tau lesion propagation and maturation. The host-injection design matrix therefore constitutes an excellent paradigm for unraveling how early seeding events mature into mature pathology.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section3\"\u003e\u003ch2\u003e3.2.3 Tau Seeding Cell Type Specificity\u003c/h2\u003e\u003cp\u003eA recurring theme among such studies is that different tau strains have a preferential targeting of cellular populations. In PS19 mice, Boluda et al. (2015) observed CBD‑derived tau selectively inducing oligodendroglial inclusions, which at one month post-injection could be visualized in hippocampal fimbria (66% of animals) and subcortical white matter (50%) but were infrequent in neurons. By contrast, AD and DSAD tau preparations induced robust neuronal perikaryal pathology, AT8- and MC1‑positive pre‑tangles and NFT‑like deposits, within CA1, CA3, dentate gyrus, and more widely, with extensive spread through entorhinal cortex, locus coeruleus, and raphe nuclei (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). No oligodendroglial tau was seen at one month in AD‑tau-injected PS19 mice, which suggests that strain conformation, rather than injection trauma per se, dictates cellular tropism.\u003c/p\u003e\u003cp\u003eClavaguera's ALZ17 transgenics built on this narrative by showing that human astrocytic phenotypes, tufted astrocytes in PSP, astrocytic plaques in CBD, and typical AGD inclusions, were faithfully recapitulated, whereas PiD homogenates, although 3R tau containing, seeded fewer filamentous structures, possibly owing to a lack of concordance between the host\u0026rsquo;s 4R‑skewed tau expression and the 3R‑dominated seed (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The fact that wild-type C57BL/6 mice also developed tau inclusions, though less frequently, suggests that endogenous murine tau can be incorporated into pathologic assemblies, obfuscating the species barrier in a quantitative sense. The detailed characteristics of the included studies, including inoculum source, host model, injection paradigm, and outcome measures, are summarized in Table\u0026nbsp;1.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Spatiotemporal Propagation Patterns\u003c/h2\u003e\u003cp\u003eIn addition to cell type bias, anatomical patterns of tau dissemination are informative of underlying mechanisms. Clavaguera et al.'s data show that most tauopathies, once seeded, spread along neuroanatomical paths: hippocampal filaments spread to the optic tract, medial lemniscus, and amygdala six months after injection. Only PiD seeds were limited, perhaps due to the lack of available compatible tau isoforms in the host. Similarly, AD/DSAD tau in PS19 mice exhibited time- and dose-dependent spread in a connectome-congruent pattern, with contralateral hippocampal involvement by three to six months (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). These observations were extended by Narasimhan et al., who showed that injection site, hippocampus versus thalamus, determines the final anatomical spread of AT8-positive pathology, once more consistent with network connectivity, rather than strain identity, determining the topography of neurodegeneration at late stages (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec23\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Conformational and Biochemical Strain Features\u003c/h2\u003e\u003cp\u003eStrain‑specific conformers are not merely intellectual curiosities but have unique biochemical signatures. Kaufman et al. delineated 18 tau strains (DS2-DS19) and showed each has unique limited‑proteolysis digestion profiles and in vitro seeding kinetics. High split‑luciferase activity strains, such as: DS6, DS9, elicited general, fast‑spreading in vivo pathology, whereas low‑seeding strains (DS2, DS3, DS11, DS19) induced \"rare seeding\" localized phenotypes. Importantly, some strains elicited astrocytic plaque deposition or rod‑shaped microglial activation, previously thought to be human subtype‑exclusive pathologies, mandating that conformational subtleties encode cell type tropism (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eFerrer et al. added a new twist to explain that homogenates from what seemed to be 4R tauopathies (GGT) could seed 3R tau deposition in hTau mice, and vice versa, that host splicing machinery was hijacked by arriving seeds to modulate exon 10 inclusion. This control of splicing could have a dramatic impact on cytoskeletal stability and synaptic function, and demonstrates that tauopathy models will now need to consider dynamic host-seed interactions, not mere static isoform complements.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003e3.6 Neurodegeneration, Gliosis, and Functional Outcomes\u003c/h2\u003e\u003cp\u003eIt would be easy to consider tau seeding a passive histopathological curiosity, but several studies associated aggregation with neuron loss, gliosis, and synaptic dysfunction. Boluda et al. observed time-dependent CA3 neuron loss in PS19 mice injected with AD/DSAD-tau but did not observe overt cell death following CBD-tau injections despite clear oligodendroglial pathology. Narasimhan et al. observed that PSP-tau induced much more AT8 inclusions and astrocytic tau transmission in non-Tg mice than AD or CBD seeds, possibly anticipating increased neurotoxicity. Microglial activation patterns were also varied: some Kaufman strains induced rod-shaped microglia in the ipsilateral hippocampus, but others made microglia quite inactive, implying that tau conformation determines the involvement of the innate immune system. In a related field, Ondrejcak et al. demonstrated that acute inhibition of hippocampal long-term potentiation in rats was caused by aqueous extracts of AD and PiD brains, that this dysfunction in synaptic function was reversible by immunodepletion of either Aβ or tau, and that chronic LTP dysfunction, assayed two to four weeks later, had concomitant immunodepletion profiles, which suggested that diffusible tau species, perhaps oligomeric rather than fibrillar, chronically exert synaptotoxicity. Of interest, with co-injection of subthreshold volumes of several different AD extracts, their combined effects were adequate for deranging plasticity, suggesting synergistic interaction of tau and Aβ, an interaction still contentious but of self-evident significance to Alzheimer\u0026rsquo;s disease pathogenesis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec25\" class=\"Section2\"\u003e\u003ch2\u003e3.7 Amyloid-binding and maturation properties\u003c/h2\u003e\u003cp\u003eThe structure of tau aggregates also varies between strains. MC1 and TG3 immunoreactivities, pathological conformation markers, emerge early in AD/DSAD-tau injections, with thioflavin-S positivity for β-sheet-enriched fibrillar inclusions. CBD-tau aggregates are MC1-positive but thioflavin-negative even after six months, consistent with human CBD pathology where oligodendroglial coiled bodies are non-amyloidogenic (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Taniguchi et al. (2024) extended these results by using an anti-N368 antibody to map C-terminal tau fragments, demonstrating that astrocytic plaques in CBD are non-N368 immunoreactive, while tufted astrocytes in PSP are intensely N368-positive (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Such proteolytic fingerprints also demonstrate that disease-defining fibril folds not only specify aggregation but also protease susceptibility and immune recognition.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec26\" class=\"Section2\"\u003e\u003ch2\u003e3.8 Serial Propagation and Model Refinement\u003c/h2\u003e\u003cp\u003eClavaguera et al. offered the most compelling evidence that tau seeds can be serially propagated. Homogenates from previously inoculated ALZ17 mice carrying human P301S tau, upon re-inoculation into naive hosts of either ALZ17 or C57BL/6, communicated neuronal and oligodendroglial disease with conservation of defining features, such as coiled bodies and neuropil threads. This serial passage is prion-like and promises high-throughput strain definition, subject to the caveat that passage through the murine host might entail adaptation artifacts of no concern for human disease progression.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec27\" class=\"Section2\"\u003e\u003ch2\u003e3.9 Risk-of-Bias\u003c/h2\u003e\u003cp\u003eWhen assessed for risk of bias through the SYRCLE risk of bias tool, we observed that the included studies were generally mixed in many domains, with several domains frequently rated as unclear. The overall ratings are summarized in Table\u0026nbsp;2, while domain‑level details are provided in Supplementary Appendix B. Taniguchi et al. (2024), Narasimhan et al. (2017) were found to have high risk of bias related to sequence generation, allocation concealment, and outcome assessment. On the other hand, the risk of bias related to baseline characteristics was at a low risk across all studies. The studies conducted by Hosokawa et al. (2022), Clavaguera et al. (2013), Ferrer et al. (2022), and Ondrejcak et al. (2023) primarily had unclear risk of bias across domains related to randomization, housing, and blinding domains. However, they were at a low risk of bias for incomplete outcome data. Kaufman et al. (2016) had a high risk of bias in baseline characteristics. On the other hand, the risk of bias for outcome assessment and reporting was low. For the study conducted by Boluda et al. (2015), the risk of bias was low across several domains. In contrast, Boluda et al. (2015) had a high risk of bias for post‑injection housing. Overall, selective outcome reporting was generally low risk, and incomplete outcome data were well managed across most studies.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cdiv id=\"Sec29\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Summary of Main Findings\u003c/h2\u003e\u003cp\u003eThis systematic review of eight head-to-head comparative studies highlights the prion-like behavior of tau strains in rodent models, shedding light on how primary tauopathies, those predominated by 3R or 4R tau isoforms, and secondary tauopathies, those with mixed 3R/4R compositions, differentially spread pathology in vivo. Across various sites of inoculation, such as hippocampus, cortex, striatum, and thalamus, and observation intervals between 1 to 15 months, a clear picture reveals itself: human brain-derived tau seeds not just induce aggregation but also preserve isoform-specific as well as cell-type tropisms characteristic of their originating diseases. For example, seeds of primary 4R tauopathies such as corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) almost exclusively target glial cells, producing astrocytic plaques as well as oligodendroglial coiled bodies, whereas seeds with mixed 3R/4R isoforms from Alzheimer's disease (AD) preferentially promote neuronal neurofibrillary tangles (NFTs) with associated neurotoxicity, including extensive CA3 neuron loss in models such as PS19 transgenic mice (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Such effects were robust, transcending host genotypes, varying between tau overexpressing transgenics to CRISPR-engineered humanized models, and injection paradigms, emphasizing a priori conformational dictate of a seed over a composition of isoforms of pathology, cell preference, as well as anatomical spread over neuroanatomical pathways as opposed to diffusion per se.\u003c/p\u003e\u003cp\u003eNotably, this review emphasizes the heritable nature of tau strains, as seen with studies of serial propagation experiments in which induced pathologies preserved disease-specific characteristics upon transmission to na\u0026iuml;ve hosts (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Biochemical signatures, including differential protease resistances at residue N368 and amyloid-binding capabilities, further validate conformational fidelity (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Functional endpoints, albeit less uniformly assessed, link certain strains to synaptic dysfunction and gliosis, with AD extracts suppressing long-term potentiation in rat models, a reversible effect by removal of tau or Aβ by immunodepletion, indicating both Aβ- and tau-mediated synergistic interactions in mixed pathologies (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Overall, these results argue in favor of a form of a priori protective barrier between isoforms, such that primary strains having a predilection for a glial tropism, with secondary ones having a neuronal predominance. While no overt meta-analysis was possible owing to methodological variety, narrative synthesis identifies high consistency for strain-specific behavior, albeit moderate certainty owing to a priori non-human origin of this body of evidence. This synthesis refines earlier conceptualizations of tau as a prionoid protein and extends the concept by demonstrating a role for isoform barriers, as well as host-seed dynamics in a living state in vivo (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec30\" class=\"Section2\"\u003e\u003ch2\u003e4.2 Interpretation of the findings\u003c/h2\u003e\u003cp\u003eAcross the head-to-head in vivo comparisons included in this review, the most defensible interpretation is that tau seed conformation is the primary determinant of downstream pathology, while the host environment (isoform availability, genotype, and connectivity) governs the degree and pattern of recruitment. Primary, isoform-dominant seeds (3R or 4R) consistently reproduce cell-type tropisms characteristic of their human diseases (glial predominance for many 4R seeds; neuronal predominance for mixed AD seeds), and serial passage preserves these defining features, supporting a heritable, strain-encoded signal rather than a stochastic aggregation process.\u003c/p\u003e\u003cp\u003eThe directional results (strain \u0026rarr; cell-type preference; strain\u0026thinsp;+\u0026thinsp;host \u0026rarr; anatomical spreading) agree across various host backgrounds and sites of injections, revealing reproducible biological signals. Effect sizes and time courses, on the other hand, vary with host genotype, extraction technique, and post-inoculation time interval, so a high consistency exists for direction but moderate one is present for magnitude and temporal dynamics. It is a pattern that permits us to deal with the seeding hypothesis as a mechanistic model that, in principle, reproducible yet is experimentally context sensitive.\u003c/p\u003e\u003cp\u003eStructural and biochemical fingerprints (distinct protease resistance, C-terminal fragments, amyloid-binding properties) provide a plausible molecular basis for tropism: specific fibril folds likely determine cellular uptake, recruitment kinetics, and proteostatic handling by neurons versus glia. Host responses appear to act as amplifiers or brakes on seeding. Together these lines of evidence support a bidirectional model: seeds template conformation, and the host cell milieu, isoform repertoire, proteases, and immune state, transforms that template into the observed anatomical and functional phenotype.\u003c/p\u003e\u003cp\u003eThis synthesis DOES NOT claim that propagation in rodents exactly reproduces human disease timelines, clinical phenotypes, or full comorbidity interactions, nor does it claim that all experimental seed preparations are interchangeable. It rather defines a reproducible mechanistic correlate (strain-specific templating modulated by host factors) and delimits uncertainties (magnitude, timing, and clinical generalizability).\u003c/p\u003e\u003cp\u003eIn controlled in vivo comparisons, evidence holds that tauopathies are best conceptualized as strain-driven disorders where phenotypic variability arises as a product of the interactions between host biology and seed conformation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec31\" class=\"Section2\"\u003e\u003ch2\u003e4.3 Comparison With Previous Evidence\u003c/h2\u003e\u003cp\u003eOur findings resonate with the growing body of literature on tau propagation, specifically in emphasizing the prion-like hypothesis originally explained in studies that described the templated misfolding and subsequent cell-transmissive tau aggregates (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Earlier research on other strains with synthetic preformed fibrils (PFFs), for instance, did establish strain-like diversity but in an in vitro setting, or using artificially modeled aggregates that would be insensitive to the heterogeneity in seed-derived samples from human sources (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). By reviewing head-to-head analyses comparisons patient brain-derived inocula, however, the present review constructs more in vivo evidence for seed-based propagation from CBD or PSP with more direct in vivo similarity in that these seeds do actually induce pathologic gliosis in a manner that parallels human tauopathies where 4R tau is the only species predominantly found in glial inclusions (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). There is consistency with Wenger et al. (2023), who documented symptomatic progression in tauopathy models following aggregate injection, to which our review would highlight isoform-specific limitations in 4R-dominant hosts using PiD (3R type), a phenomenon less emphasized in prior overviews that focused on AD-centric mixed tau (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eDiscrepancies with previous reviews arise in the context of host modulation. For example, while Robert et al. (2021) reported strain-specific propagation in human tau models, they did not systematically compare primary versus secondary strains, potentially underestimating the role of glial tropism seen here in non-transgenic mice (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Similarly, Jang et al. (2024) demonstrated seeding in genetically modified mice expressing human tau, aligning with our observations of enhanced 3R propagation in humanized environments like hTau or CRISPR models (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). However, differences in study dates and designs, earlier works like Clavaguera et al. (2014) using peripheral administration to trigger central tauopathy, suggest that central inoculations in our included studies may accelerate pathology but compress timelines, potentially exaggerating spread compared to slower, endogenous progression in human diseases (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHowever, theoretical discrepancies remain with respect to the \u0026ldquo;prion-like\u0026rdquo; label. While our findings verify self-propagation and heritability (Kaufman et al., 2016), they refute homogeneous models by incorporating the role of splicing shifts induced by seeds (Ferrer et al., 2022), which have historically been overlooked in favor of conformational determinism alone (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Instead, it aligns with the more recent findings in in the cryo-EM studies, validating different filament structures in AD versus CBD, accounting for differences in protease sensitivity (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), yet our review incorporated more in vivo evidence on behavioral differences, like microglial activation patterns varying by strain (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Compared to guidelines from neuropathological societies, which classify tauopathies on the basis of inclusion morphology (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), it appears from the scope of our interest and the findings of this review that inoculation models could refine diagnostics by predicting strain behaviors, though discrepancies with synthetic fibrils (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) indicate human-derived seeds offer superior fidelity. Ultimately, these comparisons support a shift in the conversation from mere aggregation to strain-host interplay, resolving some debates on tau\u0026rsquo;s pathogenicity while opening others on translational applicability.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec32\" class=\"Section2\"\u003e\u003ch2\u003e4.4 Mechanistic Insights\u003c/h2\u003e\u003cp\u003eMechanistically, these findings reveal that tau strain conformations encode cellular tropism through structural elements that direct cellular uptake, recruitment, and maturation. By biological plausibility, establish prions paradigms where quaternary folds encode host interaction (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), with CBD\u0026rsquo;s legumain resistance at N368 preserves non-amyloid glial inclusions aggregates versus AD\u0026rsquo;s cleavage susceptibility yields amyloid-positive NFTs (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Host factors mediate these processes through splicing feedback, potentially by PiD\u0026rsquo;s upregulation of 3R gene expression, enhancing self-propagation (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), a mechanism also suggested in aberrant in human tauopathies' alternative splicing dysregulation (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Neuroinflammatory responses, suggested from the strain-varying microglial morphologies, could also mediate shape vulnerability, although underexplored investigated within these studies (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Synergies with co-pathologies, such as Aβ-tau interactions perturbing and disrupting LTP function, instead imply convergent pathophysiological mechanisms in secondary (mixed) tauopathies (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), inline with hypotheses of oligomeric tau\u0026rsquo;s synaptotoxicity (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Altogether, these perspectives suggest a bidirectional model, in which seeds template pathology, with the host then refining it through proteostasis and connectivity, explaining clinical diversity beyond simple diffusion.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec33\" class=\"Section2\"\u003e\u003ch2\u003e4.5 Heterogeneity\u003c/h2\u003e\u003cp\u003eHeterogeneity among the studies reviewed, due to differences in seed preparations, models of inoculation, and read-outs, is likely to affect the observed outcomes but does not detract from the core strain-specific patterns. Of course, overexpression of tau in the PS19 mouse background could amplify pathology burdens, lowering seeding thresholds and potentially inflating glial involvement in CBD injections compared to physiological expression in CRISPR models (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Between-population differences, such as species-specific isoform ratios (murine 4R-dominant models limit 3R PiD propagation), also play a role, together with intervention durations (up to 15-month observation), where mature spreading along connectomes is apparent (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). All these also resonate with the issue in tauopathy research in general, where reproducibility is affected by research methodologies (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec34\" class=\"Section2\"\u003e\u003ch2\u003e4.6 Strengths and Limitations\u003c/h2\u003e\u003cp\u003eStrengths in this review arise in its focus on head-to-head study designs, so direct comparisons for strains can be made while avoiding confounding factors, an improvement over more general tauopathy reviews (Kovacs, 2015). The extensive database search combined with the various rodent models is key for preclinical setting generalizability, with narrative syntheses accommodating any heterogeneity, allowing for a complex understanding regarding prion-like fidelity (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Also, one of the key strengths in our review is that it included studies that utilized appropriate biochemical validation tests that improve the quality of evidence by potentially avoiding artifactual seedings (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHowever, these findings are also subject to some limitations, with only eight studies included (n\u0026thinsp;=\u0026thinsp;8), and the lack of meta-analyses and formal bias assessments like funnel plots. However, methodological heterogeneity, the varied extractions, genotypes, and timelines, makes the cross-study synthesis subject to discrepancies among the studies, such as the propagation efficiencies (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Our English-language restriction and exclusion of synthetic PFFs introduced publication and scope biases (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). The certainty of our findings is limited by weaknesses in the methodology of the included studies. Several domains, particularly randomization, blinding, and housing, were frequently rated as unclear or high risk, which may have inflated observed effects. Nevertheless, outcome reporting and handling of incomplete data were generally low risk, lending some confidence to the overall trends. Other study-level limitations include: small sample sizes, and reliance on rodent models that may not capture human comorbidities or aging (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec35\" class=\"Section2\"\u003e\u003ch2\u003e4.8 Clinical, Policy, and Theoretical Implications\u003c/h2\u003e\u003cp\u003eClinically, these findings prove that targeting conformers, strain-specific, could be a force of change in tauopathies therapies, such as isoform-selective antibody approaches to stop glial versus neuronal transmission in primary versus secondary diseases (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). In AD, therapies for mixed tau could target synaptic protectors, with CBD/PSP targeting glial modulators, guiding precision therapies in tandem with prion disease approaches (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Policy makers could then advocate for standardized in vitro protocols to expedite translation efforts, possibly impacting funding and budgeting priorities for more accurate and efficient humanized models (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Theoretically, our findings pose a challenge to reductionist models of understanding tau as a uniform homogeneous protein, and extending into the larger proteinopathies conversation where the interactivity between the host and strain is correlational in terms of heterogeneity, closing the gap with synucleinopathies versus amyloids (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Net benefits for strain identification outweigh any possible harm in artifact variance in rodent models interpreted in human trials (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec36\" class=\"Section2\"\u003e\u003ch2\u003e4.9 Future Research Directions\u003c/h2\u003e\u003cp\u003eFuture investigations should instead emphasize protocol standardization, especially standardized seed characterization through cryo-EM, proteomics for meta-analyzing (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), more complex models incorporating aging factors and comorbidity, such as, Aβ and tau (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Longitudinal studies using multimodal endpoints for imaging, behavioral, and electrophysiological measurements could attempt correlations between propagation events and their contribution to cognitive and functional outcomes (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Mechanistic studies into glial cell-based propagation strategies could identify treatment approaches, while comparing aggregate differences between humans and animals using direct comparison protocols in cryo-EM would validate (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eEvidence from the present systematic review supports the notion that tau seeds derived from primary (3R- or 4R-dominant) and secondary (mixed 3R/4R) tauopathies of humans preserve their isoform- and cell type-specific pathologies in rodent models in a manner where glial cell tropism is a characteristic feature in principle for strains derived from corticobasal degeneration and progressive supranuclear palsy tauopathies, with neuronal preference for neurofibrillary tangles in Alzheimer\u0026rsquo;s disease-derived strains. The phenotypic diversity in these strains is thus reflected in their adaptability to their states as either seed-cores or mimetic molecules in their surroundings.\u003c/p\u003e\u003cp\u003eThe certainty of evidence is only moderate, with heterogeneity in research methodology across the eight studies making direct comparison unfeasible for meta-analysis, potentially leading to uneven comparison factors. Additionally, its non-human preclinical focus limits direct applicability to humans, where age-related comorbidities and complex co-pathologies like amyloid-β interactions are commonplace, potentially underestimating translational challenges. Also, within-study factors in the original research, particularly in studies with smaller sample sizes, affect these certainties somewhat, even with head comparison studies.\u003c/p\u003e\u003cp\u003eAt a clinical level, these findings argue for the need for strain-specific diagnostics and treatment strategies; neurologists could initially target glial cells in primary tauopathies versus synaptic protectors in secondary tauopathies. Policymakers should support higher research budgets for more reproducible protocols in animal models to collectively mitigate the currently unbeatable nature of tauopathies, as discussed in more general analyses. Researchers should combine these models with human data to produce more informed predictions rather than rely on the rapidly accelerated timelines that may not accurately represent disease in humans.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cb\u003eFunding Declaration\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not‑for‑profit sectors.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u0026bull; \u003cb\u003eClinical Trial Number\u003c/b\u003e: not applicable.\u003c/p\u003e\u003cp\u003e\u0026bull; \u003cb\u003eConsent to Publish Declaration\u003c/b\u003e: not applicable.\u003c/p\u003e\u003cp\u003e\u0026bull; \u003cb\u003eConsent to Participate Declaration\u003c/b\u003e: not applicable.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eM.A.W. and A.K.B. conceived the study design and wrote the main manuscript text.M.S. and A.T. performed the systematic search and data extraction.A.H. and A.Y.E. conducted risk‑of‑bias assessment and prepared summary tables.A.H.A. and A.G.E. synthesized results and drafted the discussion section.M.E. and A.E. prepared figures and formatted references.All authors (M.A.W., A.K.B., M.S., A.T., A.H., A.Y.E., A.H.A., A.G.E., M.E., A.E.) reviewed the manuscript and approved the final version.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eIn line with open-science principles, we will also make our entire extraction database, systematic risk-of-bias tables, subgroup-analysis comments, and narrative synthesis tables available on the Open Science Framework (OSF). All these resources will have a distinct DOI and will be published under a Creative Commons Attribution (CC BY) license to facilitate independent verification and secondary analyses.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAhmed Z, Cooper J, Murray TK, Garn K, McNaughton E, Clarke H, et al. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: The pattern of spread is determined by connectivity, not proximity. Acta Neuropathol. 2014;127(5):667\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRobert A, Sch\u0026ouml;ll M, Vogels T. Tau Seeding Mouse Models with Patient Brain-Derived Aggregates. Int J Mol Sci. 2021;22(11):6132.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHan ZZ, Kang SG, Arce L, Westaway D. Prion-like strain effects in tauopathies. 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Science. 2020;367(6479):84\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJang E, Hoxha K, Mozier D. Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread. Journal of Neuroscience [Internet]. 2024;44(48). Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1523/JNEUROSCI.0877-24.2024\u003c/span\u003e\u003cspan address=\"10.1523/JNEUROSCI.0877-24.2024\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHosokawa M, Masuda-Suzukake M, Shiina H, Ookami H, Shimozawa A, Kondo H, et al. Development of a novel tau propagation mouse model endogenously expressing 3 and 4 repeat tau isoforms. Brain. 2022;145(1):280\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCampbell M, McKenzie JE, Sowden A, Katikireddi SV, Brennan SE, Ellis S, et al. 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Transl Neurodegener. 2024;13:40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNath S, Agholme L, Kurudenkandy FR, Granseth B, Marcusson J, Hallbeck M. Spreading of neurodegenerative tau protein in the brain. J Intern Med. 2012;271(6):518\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWenger K, Viode A, Schlaffner CN. Common Mouse Models of Tauopathy Reflect Early but Not Late Human Disease. Mol Neurodegener. 2023;18:10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMietelska-Szadkowska K. Tau protein and tauopathies. I. Function and structure of tau protein. Folia Neuropathol. 2020;58(2):87\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSharma AM, Saiardi A. Recombinant tau protein aggregates: preparation and use. Methods Mol Biol. 2022;2521:235\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8090222/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8090222/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eTauopathies are a heterogeneous group of neurodegenerative disorders characterized by a pathological tau aggregation. Each disorder is defined by distinct isoform content (3R, 4R, or mixed 3R/4R), which dictates cell-type susceptibility, pathologic propagation, and clinical symptomatology. How these strains propagate in vivo will be critical to developing translational models and therapies.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eFollowing SWiM guidelines, we performed a systematic review with the protocol registered on PROSPERO (CRD420251053445). PubMed, Scopus, and Web of Science (inception - May 2025) searches identified studies directly comparing human brain-derived primary and secondary tau seeds in rodent models. Inclusion criteria required stereotactic intracerebral inoculation, comparable protocols, and reporting of inclusion burden, propagation, or isoform recruitment. SYRCLE tool was employed to assess the risk of bias.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFrom the 1,437 screened records, 8 studies were eligible. Propagation in various rodent models was strain consistent: 4R-dominant seeds (CBD, PSP) selectively induced glial inclusions, while mixed AD-derived seeds induced neuronal neurofibrillary tangles with associated neurotoxicity. Isoform-selective recruitment, protease resistance to cleavage at particular sites, and amyloid-binding provided biochemical counterparts of tropism. Serial passage experiments confirmed heritability of strain features. Functional consequences included synaptic dysfunction, gliosis, and neuronal loss, whose spread patterns were host genotype- and time-of-observation-dependent. Risk-of-bias was mixed, with frequent unclear domains.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThese findings support a two-way model in which tau strain conformation dictates cellular tropism, and host biology controls magnitude and distribution, and reinforce the prion-like model of tau transmission. Future work needs to prioritize standardized protocols, advanced humanized models, and multimodal functional readouts.\u003c/p\u003e","manuscriptTitle":"Comparative Analysis of Primary (3R/4R) versus Secondary (3R + 4R) Tauopathy Strains in Rodent Models: A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-02 08:45:26","doi":"10.21203/rs.3.rs-8090222/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c78ccd95-7bcc-442c-83a5-64895376dd99","owner":[],"postedDate":"December 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-29T10:23:20+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-02 08:45:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8090222","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8090222","identity":"rs-8090222","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}