Single-cell Spatial Transcriptional Profiling Uncovers Heterogeneous Cellular Responses to Pathogenic Tau in a Mouse Model of Neurodegeneration

doi:10.1101/2025.11.19.689127

Single-cell Spatial Transcriptional Profiling Uncovers Heterogeneous Cellular Responses to Pathogenic Tau in a Mouse Model of Neurodegeneration

2025 · doi:10.1101/2025.11.19.689127

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The paper used CosMx SMI single-cell spatial transcriptional profiling of over 265,000 cells, assessing 950 genes in rTg(tauP301L)4510 mouse brains with tauopathy and in controls. It found that in the cerebral cortex, tau pathology disrupts the excitatory-inhibitory balance and alters pathways important for myelination, with similar myelin-associated changes reported in patient tissue from progressive supranuclear palsy; in the hypothalamus, tau accumulation correlated with transcriptional changes tied to pathways regulating body weight and metabolism. A major limitation is that the study is based on a mouse tauopathy model and a selected gene panel measured via spatial profiling, so findings reflect those system and measurement constraints. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Summary Intracellular tau accumulation contributes to neurodegeneration and systemic dysfunction. Although tau primarily aggregates in neurons as neurofibrillary tangles (NFTs), it also affects other cell types through poorly understood mechanisms. To define the molecular characteristics of tangle-bearing neurons and their influence on surrounding cells, we used CosMx SMI to evaluate the expression of 950 genes in more than 265,000 cells from rTg(tauP301L)4510 tauopathy and control mouse brains. In the cerebral cortex, tau pathology disrupted the excitatory-inhibitory neuron balance and altered pathways critical for myelination, similar myelin changes were observed in postmortem brain tissue from patients with progressive supranuclear palsy. In the hypothalamus, tau accumulation was associated with transcriptional changes linked to pathways involved in body weight and metabolic regulation. These findings reveal molecular mechanisms underlying both cell-autonomous and non-autonomous effects of tauopathy and identify targets for further investigation into tau pathogenesis and its systemic impact. Competing Interest Statement M.E.O. has a patent pending, 'Detecting and Treating Conditions Associated with Neuronal Senescence' unrelated to this work. M.E.O. is the Director of a Bruker Spatial Biology Center of Excellence. L.W., A.H., K.Y., N.D., J.C.N and J.M.B. are or were employees of NanoString Technologies (now Bruker Spatial Biology, Inc.). The other authors declare no competing interests in relation to this work. Footnotes Xuehan Sun: sxuehan{at}wustl.edu, Lidan Wu: Lidan.Wu{at}bruker.com, Timothy C. Orr: orrt{at}wustl.edu, Ashley Heck: Ashley.Heck{at}bruker.com, Kimberly Young: Kimberly.Young{at}bruker.com, Nathan Dunaway: nathandunaway{at}hotmail.com, Jose Ceja Navarro: cejanavj{at}gmail.com, Joseph M. Beechem: Joseph.Beechem{at}bruker.com, Miranda E. Orr: orr.m{at}wustl.edu

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