Myeloid FSH-FSHR signaling drives menopause-associated cognitive decline via a mitochondrial RNA-dependent neuroinflammation axis

Myeloid FSH-FSHR signaling drives menopause-associated cognitive decline via a mitochondrial RNA-dependent neuroinflammation axis | 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 Biological Sciences - Article Myeloid FSH-FSHR signaling drives menopause-associated cognitive decline via a mitochondrial RNA-dependent neuroinflammation axis Jiajun Zhao, Yuan Li, Xinyu Zhang, Weihao Li, Dawei Wang, Haiqing Zhang, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8773348/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 Menopause-associated cognitive decline is a pervasive health challenge for women, intricately linked to neuroinflammation, yet the precise immunometabolic mechanisms remain largely elusive. Here, we found that follicle-stimulating hormone (FSH) directly promotes neuroinflammation and cognitive deficits in a mouse model of menopause. We uncover that FSH signaling in myeloid cells triggers the cytosolic leakage of mitochondrial RNA (mtRNA) by reducing NAD+ capping at its 5′ or 3’-end. This aberrant mtRNA accumulation subsequently activates the TBK1–IRF3–IFNβ axis. Critically, the RNA-editing enzyme ADARB2 emerges as a key downstream effector of FSH, governing mtRNA localization and double-stranded RNA (dsRNA) formation. Myeloid-specific deletion of Fshr or Adarb2, or pharmacological inhibition of ADARB2 with 8-Azanebularine, robustly rescues neuroinflammation and cognitive impairment in ovariectomized mice. Furthermore, exogenous administration of NAD+-capped mtRNA attenuates FSH-driven neuroinflammation. Our findings define a pathogenic FSH–FSHR pathway in menopause, challenging estrogen-centric views of brain aging, and identify ADARB2 inhibition and NAD+-mtRNA integrity as potent non-estrogenic therapeutic strategies for menopause-associated cognitive decline. Health sciences/Endocrinology/Endocrine system and metabolic diseases Health sciences/Neurology/Neurological disorders Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Women experience age-related cognitive decline and Alzheimer's disease (AD), facing a higher lifetime risk and more rapid disease progression than men 1 . This marked increase in incidence post-menopause has long implicated the hypothalamic-pituitary-gonadal axis, with the decline in ovarian estrogens extensively studied 2,3 . However, the ambiguous therapeutic efficacy and potential oncogenic risks of estrogen replacement therapies underscore a critical gap in our understanding and an urgent need for safer, non-estrogenic therapeutic targets 4 . The menopausal transition is not solely characterized by estrogen withdrawal; it is also marked by a profound hypergonadotropic state, evidenced by a substantial and persistent increase in circulating FSH and luteinizing hormone (LH) 5,6 . While estrogen's role has dominated the discourse, the direct impact of this sustained FSH elevation on brain function, particularly its contribution to cognitive decline, remains a critical unresolved question. Aging invariably induces a persistent, low-grade inflammatory state within the central nervous system (CNS), a significant contributor to neurodegeneration 7 . Emerging evidence highlights the bone marrow as a crucial source of myeloid cells that migrate to the aging brain, suggesting a pivotal role for peripheral immune factors in brain aging 8 . Yet, the specific systemic signals that prime these myeloid cells to adopt a pro-aging, neuroinflammatory profile have remained elusive. Concurrently, the type I interferon (IFN-I) pathway is recognized as a conserved and deleterious driver of brain aging, frequently activated by the abnormal cytosolic presence of self-nucleic acids 9,10 . Mitochondria, evolutionary remnants of bacterial ancestry, represent a potent source of such immunogenic molecules, notably dsRNA. Under physiological conditions, the immunogenic potential of mtRNA is mitigated by strict compartmentalization and crucial nucleotide modifications, such as NAD+ capping 11,12 . The mechanisms that maintain mtRNA integrity and prevent its detrimental cytosolic leakage during aging, represent a critical gap in our current understanding. Here, we propose a novel pathogenic axis: the menopausal increase in FSH leads to reprogram myeloid cells to initiate neuroinflammation and cognitive impairment. Our comprehensive investigation reveals that FSH signaling via its receptor (FSHR) on myeloid cells triggers a cascade of events, leading to the upregulation of adenosine deaminase ADARB2. We demonstrate that ADARB2 disrupts NAD+ capping and facilitates the cytosolic leakage of mtRNA, subsequently activating the TBK1-IRF3-IFNβ signaling pathway. Our findings unveil a definitive FSH-IFN-I axis, providing a direct molecular link between the peripheral endocrine environment of menopause and maladaptive innate immune responses in the brain. This study not only offers a mechanistic explanation for the heightened susceptibility of females to cognitive decline but, crucially, identifies both ADARB2 and NAD+-capped mtRNA integrity as compelling, non-estrogenic therapeutic targets for intervention. Results Bone marrow-derived myeloid cells are indispensable for menopause-associated neuroinflammation and cognitive deficits To systematically investigate the structural alterations in the brain during menopause, we established an ovariectomy (OVX) model in adult 9-month-old female mice. Diffusion tensor imaging (DTI) revealed significant changes, with a decrease in fractional anisotropy (FA) values and elevated mean diffusivity (MD) in the cingulate gyrus (CG) and anterior cingulate cortex (ACC) of OVX mice (Fig. 1a–f). These DTI findings, coupled with the upregulation of inflammatory markers (Il-1β, Ccl2, B2m) in the ACC (Fig. 1g), suggest tissue edema and robust neuroinflammatory responses following ovariectomy. To delineate the contribution of bone marrow-derived myeloid cells, we employed an AAV9 vector expressing GFP under the F4/80 promoter in the bone marrow. Histological analysis revealed a pronounced increase in GFP⁺ cell infiltration into the ACC of OVX mice (Fig. 1h–i). Critically, myeloid cell depletion using intraosseous clodronate liposomes (Clo) abrogated recognition memory impairment, rescued deficits in cued fear conditioning and spatial learning, and attenuated OVX-induced microglial activation and dendritic spine loss in the ACC (Extended Data Fig. 1a–j). These results establish myeloid cells as essential mediators of ovariectomy-induced neuroinflammation and associated cognitive decline. Elevated FSH levels critically drive menopause-associated cognitive decline via myeloid cell-related neuroinflammation To dissect the direct role of FSH in this process, we employed a gonadotropin-releasing hormone analog (GnRHa) to suppress endogenous gonadotropins 13 , followed by exogenous FSH administration to selectively mimic post-menopausal hypergonadotropism while maintaining stable estradiol levels (Extended Data Fig. S2a–c). GnRHa treatment rescued memory deficits in NOR, CFC, and MWM tests, a protective effect entirely abolished by exogenous FSH supplementation (Extended Data Fig. S2d–g). FSH administration also exacerbated microglial activation (Extended Data Fig. S2h–i). These results reveal that FSH levels play a determinant role in menopause-related cognitive decline. Furthermore, a doxycycline (Dox)-inducible FSH β subunit overexpression model (Fshβ-KI) in ovariectomized, E2-replete mice confirmed that elevated FSH, independent of estrogen fluctuations (Fig. 2a-d), significantly increased the infiltration and proinflammatory activation (CD80⁺, MHC-II⁺) of GFP⁺ myeloid cells in the brain (Fig. 2a–h). Live imaging dramatically visualized enhanced myeloid cell motility and accumulation in the ACC under high FSH conditions (Fig. 2i–k; Extended Movies 1–2). These findings provide compelling evidence that FSH directly promotes the infiltration and proinflammatory activation of myeloid cells in the brain, thereby contributing to neuroinflammation and cognitive impairment in a menopausal context. Myeloid FSHR signaling restores menopausal neuroinflammation and cognitive impairment Given the pivotal role of FSH, we next investigated the therapeutic potential of attenuating myeloid FSH signaling. We generated myeloid-specific FSHR conditional knockout mice (MKO) (Extended Data Fig. 3a), and western blot analysis of purified BMDMs confirmed efficient Fshr knockdown at the protein level (Extended Data Fig. 3b). MKO reversed OVX-induced memory deficits in both NOR and MWM tests (Extended Data Fig. 3c–d). Mechanistically, MKO mice exhibited significantly reduced infiltration of CD11b⁺Ly6C⁺ monocytes into the brain and lower expression of proinflammatory markers CD86 on brain-resident macrophages (CD45⁺CX3CR1⁺) post-OVX (Extended Data Fig. 3e–h). Microglial morphology in MKO mice appeared more ramified and homeostatic with showing increased branching endpoints and reduced CD68 expression in MKO mice (Extended Data Fig. 3i–k). Crucially, MKO preserved dendritic spine density in the ACC following OVX (Extended Data Fig. 3l–m). These results demonstrate that myeloid FSHR deletion mitigates menopausal cognitive impairment by suppressing neuroinflammation and preserving neuronal structure. Single-cell RNA sequencing (scRNA-seq) on bone marrow CD11b⁺ cells from MKO mice revealed significant compositional shifts and specific gene set enrichment analysis (GSEA) indicated a suppression of inflammatory response and type I interferon signaling in a key macrophage subset (cluster 7) of MKO-OVX mice (Fig. 3a–g). This striking observation implicated myeloid FSHR in promoting IFN-I signaling. FSHR signaling in myeloid cells triggers localized IFN-I production and microglial activation in the ACC of menopausal mice To validate the connection between myeloid FSHR and IFN-I activation, we found that IFN-β concentration was significantly reduced in the ACC of MKO-OVX mice, accompanied by attenuated IRF3 phosphorylation, without affecting systemic or hippocampal IFN-β levels (Extended Data Fig. 4a–e). Using an AAV9 vector for F4/80 promoter-driven Fshr shRNA delivery to bone marrow (Fig. 4a–c), we observed that Fshr knockdown in myeloid cells ameliorated memory deficits and attenuated microglial activation, morphological changes, and local IFN-I protein levels (Fig. 4d–i; Extended Data Fig. 5a–d). Spatial analysis confirmed that Fshr knockdown inhibited STAT1 activation in CD68⁺ cells adjacent to GFP⁺ myeloid cells, a clear readout of localized IFN-I signaling (Fig. 4j–k). Collectively, these findings conclusively establish that FSHR expression in myeloid cells mediates neuroinflammation via localized IFN-I release, which directly contributes to memory impairment in menopausal mice. Restoring NAD ⁺-capped mtRNA ameliorates FSH-driven neuroinflammation To unravel the molecular underpinnings of FSH-mediated IFN-I induction, multi-omics profiling of Fsh-treated BMDMs revealed enrichment in antiviral immune signaling pathways (Extended Data Fig. 6a–b) and increased IFN-β secretion, which was abolished by Fshr knockout (Extended Data Fig. 6c). RNase pretreatment and the use of mtDNA/RNA-depleted (ρ⁰) cells confirmed that cytosolic mtRNA is indispensable for FSH-induced IFN-I pathway activation (Extended Data Fig. 6d–f). Untargeted metabolomics in FSH-treated BMDMs revealed a dose-dependent decrease in nicotinamide (NAM) and mitochondrial NAD⁺ levels (Fig. 5a–b). Importantly, FSH reduced NAD⁺-RNA capping, mimicking the effect of NAD⁺ synthesis inhibition FK866 (Fig. 5c; Extended Data Fig. 7a). Exogenous transfection of synthesized NAD⁺-capped mtRNA (NAD’-mtRNA) attenuated FSH-induced cytosolic dsRNA accumulation and suppressed IFN-β expression and IFN-I signaling (Fig. 5d; Extended Data Fig. 7b–e). In vivo , local injection of NAD’-mtRNA into the ACC of OVX mice downregulated IFN-I expression, suppressed STAT1/IRF3 activation, and reduced microglial activation (Fig. 5g–l). These results demonstrate that FSH promotes deleterious cytosolic mtRNA leakage and IFN-I activation in myeloid cells, a pathogenic process that can be effectively mitigated by NAD’-mtRNA administration, highlighting mtRNA integrity as a novel therapeutic target. ADARB2 governs mtRNA-triggered IFN-I activation and cognitive deficits in response to FSH To identify the mediator of FSH-induced dsRNA production, multi-omics analyses highlighted adenosine deaminase ADARB2 as a top differentially expressed protein (Extended Data Fig. 8a). We found that both siRNA-mediated knockdown and pharmacological inhibition of ADARB2 with 8-Azanebularine (8-Aza), a compound with high binding affinity for ADARB2 (Fig. 6a; Extended Data Fig. 8b), suppressed FSH-induced TBK1/IRF3 phosphorylation and IFN-I expression (Extended Data Fig. 8c–f). This conclusively links FSH to IFN-I signaling through ADARB2. Mechanistically, RIP-Seq confirmed an interaction between ADARB2 and mtRNA (Extended Data Fig. 9a). Genetic or pharmacological inhibition of ADARB2 increased NAD+-RNA levels, strongly suggesting that ADARB2 negatively regulates NAD⁺ capping (Extended Data Fig. 9b). Overexpression of ADARB2 enhanced cytoplasmic mtRNA and dsRNA accumulation, effects counteracted by NAD’-mtRNA supplementation (Extended Data Fig. 9c–d). These findings unveil a novel regulatory axis where ADARB2, by modulating NAD⁺ capping and subcellular localization of mtRNA, acts as a critical checkpoint for dsRNA-driven innate immune activation. Furthermore, myeloid-specific knockdown of Adarb2 in transplanted BMDMs significantly rescued OVX-induced memory deficits (Extended Data Fig. 10c–e). Using RFP to track the transplanted BMDMs, we observed that Adarb2 knockdown suppressed microglia adjacent to RFP⁺ donor cells in Ovx mice exhibited classic activation features—soma enlargement and process retraction (Extended Data Fig. 10g–i). Adarb2 knockdown decreased STAT1 expression in CD68⁺ cells near RFP⁺ cells (Extended Data Fig. 10j–k) and elevated BMDMs synaptic density per neuronal (Extended Data Fig. 10l–m). This provides robust in vivo evidence that myeloid ADARB2 is a pivotal mediator of cognitive decline in a menopausal model. Pharmacological inhibition of ADARB2 rescues cognitive deficits in menopausal mice Based on the potent inhibitory effect of 8-Aza on ADARB2, we conducted a comprehensive pharmacological intervention study (Fig. 6a-b). Systemic administration of 8-Aza profoundly ameliorated menopause-related cognitive and memory deficits across NOR, CFC, and MWM tests (Fig. 6c–e). At the molecular level, 8-Aza treatment markedly suppressed IFN-I mRNA and protein expression in the ACC, attenuated downstream IFN-I signaling, reduced microglial activation, and enhanced synaptic plasticity (Fig. 6f–m). Collectively, these results provide compelling evidence that pharmacological inhibition of ADARB2 with 8-Aza is a highly effective strategy for rescuing learning and memory impairments in a menopausal context, strongly supporting its potential as a novel therapeutic strategy. Discussion This study uncovers a definitive, previously unidentified pathway linking elevated FSH to neuroinflammation and cognitive decline via myeloid FSHR signaling and aberrant mitochondrial RNA metabolism. Our findings provide a mechanistic explanation for the heightened risk of AD in menopausal women and, crucially, identify several novel and druggable targets, including FSH itself and ADARB2, for the prevention and treatment of menopause-related cognitive disorders. The markedly higher prevalence of AD in women has largely been attributed to the decline in sex steroid hormones, particularly estrogen, following menopause. However, the molecular mechanisms underlying this sex disparity remain inadequately understood. Our findings fundamentally challenge this estrogen-centric paradigm by positioning elevated FSH as a primary etiological factor. By employing sophisticated mouse models that meticulously dissociate the effects of elevated FSH from other menopausal hormonal changes, specifically the OVX + GnRHa + FSH model and estrogen supplementation in OVX female Fshβ knock-in mice, we provide compelling evidence that FSH itself is a critical and sufficient driver of cognitive impairment, operating independently of estrogen deficiency. This offers a transformative new perspective on the hormonal drivers of postmenopausal brain aging. While extra-gonadal FSHR signaling has been implicated in bone metabolism, adiposity, and cholesterol homeostasis 14-16 , its role in the immune system and, critically, the CNS, has been obscure. Our work reveals a pivotal and previously unrecognized function for myeloid FSHR in regulating neuroinflammation. Having established that FSH signaling promotes a pro-inflammatory phenotype in myeloid cells, we elucidated how these peripheral immune cells communicate with the CNS. Bone marrow-derived myeloid cells infiltrate the brain parenchyma and, moreover, FSH signaling through FSHR on these cells is a key promoter of their infiltration and subsequent neuroinflammatory response. The indispensable role of these myeloid cells in mediating menopause-associated cognitive impairment is further underscored by their functional clearance. Upon infiltrating the brain, FSH-primed myeloid cells necessitate an intrinsic mechanism to exacerbate neuroinflammation. Our in-depth investigation into the transcriptomic and metabolic changes within these cells uncovered a surprising and critical role for RNA modification. We propose a novel mechanism whereby NAD⁺ capping of mtRNA serves as a crucial cellular self-surveillance checkpoint, preventing aberrant IFN-I activation. The FSH-mediated reduction in NAD⁺ levels compromise this checkpoint, leading to deleterious cytosolic mtRNA leakage and dsRNA accumulation. This study further elucidates the critical role of ADARB2, an RNA-editing enzyme 17 . In stark contrast to the canonical role of ADAR1 in suppressing interferon responses by editing dsRNA 18 , our findings uniquely position ADARB2 as a positive regulator of neuroinflammation in this context, likely by actively modulating the dynamics of NAD⁺-RNA and dsRNA and potentially engaging MAVS-related signaling 19 . The dramatic amelioration of cognitive deficits upon Adarb2 knockout or pharmacological inhibition unequivocally highlights its pivotal role in this pathogenic pathway and presents a highly promising therapeutic node. In conclusion, our work definitively uncovers a novel and critical pathway linking elevated FSH to neuroinflammation and cognitive decline via myeloid FSHR signaling and aberrant mtRNA metabolism. This seminal discovery not only provides a robust mechanistic explanation for the heightened risk of AD in menopausal women but, importantly, identifies ADARB2 inhibition and restoration of NAD’-mtRNA integrity as potent, non-estrogenic therapeutic strategies for the prevention and treatment of menopause-related cognitive disorders. Declarations Acknowledgements We thank the Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging (Shandong First Medical University) for consultation and instrument availability that supported this work. Author contributions YL, XZ, WL and DW designed the experiments; RZ, CL, ZR, DW, QX and LZ performed experiments; YL, XZ, XZ and HL interpreted data; YL, DW wrote the manuscript; QX, YL, TL, ZW, ZY and XF provided input on data analysis and computational approaches; HZ, QS, LF, MW and JZ undertook project management. Funding The National Natural Science Foundation of China (No. 82571360, U23A20469, 82130025, 82203819), The Natural Science Foundation of Shandong Province (No. ZR2025MS1433, ZR2023MH322, ZR2024MH290, ZFJH202306), and Shandong Provincial Higher Education Youth Innovation Team Program (No. 2024KJJ017, 2024KJJ025) supported this study. Availability of data and materials Data supporting the present study are available from the corresponding author upon reasonable request. Competing interests The authors declare no competing interests. References Fisher, D. W., Bennett, D. A. & Dong, H. Sexual dimorphism in predisposition to Alzheimer's disease. Neurobiol Aging 70 , 308-324, doi:10.1016/j.neurobiolaging.2018.04.004 (2018). Marongiu, R. Accelerated Ovarian Failure as a Unique Model to Study Peri-Menopause Influence on Alzheimer's Disease. Front Aging Neurosci 11 , 242, doi:10.3389/fnagi.2019.00242 (2019). Greendale, G. A. et al. 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Additional Declarations There is NO Competing Interest. Supplementary Files FigureS1.jpg Exended Figure 1 FigureS2.jpg Exended Figure 2 FigureS3.jpg Exended Figure 3 FigureS4.jpg Exended Figure 4 FigureS5.jpg Exended Figure 5 FigureS6.jpg Exended Figure 6 FigureS7.jpg Exended Figure 7 FigureS8.jpg Exended Figure 8 FigureS9.jpg Exended Figure 9 FigureS10.jpg Exended Figure 10 Supplementarytables.docx Supplementary tables SupplementarymovieDOX.gif Video -Dox group Materialandmethod.docx Material and methods Workingmodel.tif Extended Figure 11 SupplementarymovieDOX.gif Video +Dox group 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. 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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-8773348","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":585897854,"identity":"da366cfc-087a-4379-86cb-c72fb935c437","order_by":0,"name":"Jiajun 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This marked increase in incidence post-menopause has long implicated the hypothalamic-pituitary-gonadal axis, with the decline in ovarian estrogens extensively studied\u003csup\u003e2,3\u003c/sup\u003e. However, the ambiguous therapeutic efficacy and potential oncogenic risks of estrogen replacement therapies underscore a critical gap in our understanding and an urgent need for safer, non-estrogenic therapeutic targets\u003csup\u003e4\u003c/sup\u003e. The menopausal transition is not solely characterized by estrogen withdrawal; it is also marked by a profound hypergonadotropic state, evidenced by a substantial and persistent increase in circulating FSH and luteinizing hormone (LH)\u003csup\u003e5,6\u003c/sup\u003e. While estrogen's role has dominated the discourse, the direct impact of this sustained FSH elevation on brain function, particularly its contribution to cognitive decline, remains a critical unresolved question.\u003c/p\u003e\n\u003cp\u003eAging invariably induces a persistent, low-grade inflammatory state within the central nervous system (CNS), a significant contributor to neurodegeneration\u003csup\u003e7\u003c/sup\u003e. Emerging evidence highlights the bone marrow as a crucial source of myeloid cells that migrate to the aging brain, suggesting a pivotal role for peripheral immune factors in brain aging\u003csup\u003e8\u003c/sup\u003e. Yet, the specific systemic signals that prime these myeloid cells to adopt a pro-aging, neuroinflammatory profile have remained elusive. Concurrently, the type I interferon (IFN-I) pathway is recognized as a conserved and deleterious driver of brain aging, frequently activated by the abnormal cytosolic presence of self-nucleic acids\u003csup\u003e9,10\u003c/sup\u003e. Mitochondria, evolutionary remnants of bacterial ancestry, represent a potent source of such immunogenic molecules, notably dsRNA. Under physiological conditions, the immunogenic potential of mtRNA is mitigated by strict compartmentalization and crucial nucleotide modifications, such as NAD+ capping\u003csup\u003e11,12\u003c/sup\u003e. The mechanisms that maintain mtRNA integrity and prevent its detrimental cytosolic leakage during aging, represent a critical gap in our current understanding.\u003c/p\u003e\n\u003cp\u003eHere, we propose a novel pathogenic axis: the menopausal increase in FSH leads to reprogram myeloid cells to initiate neuroinflammation and cognitive impairment. Our comprehensive investigation reveals that FSH signaling via its receptor (FSHR) on myeloid cells triggers a cascade of events, leading to the upregulation of adenosine deaminase ADARB2. We demonstrate that ADARB2 disrupts NAD+ capping and facilitates the cytosolic leakage of mtRNA, subsequently activating the TBK1-IRF3-IFNβ signaling pathway. Our findings unveil a definitive FSH-IFN-I axis, providing a direct molecular link between the peripheral endocrine environment of menopause and maladaptive innate immune responses in the brain. This study not only offers a mechanistic explanation for the heightened susceptibility of females to cognitive decline but, crucially, identifies both ADARB2 and NAD+-capped mtRNA integrity as compelling, non-estrogenic therapeutic targets for intervention.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBone marrow-derived myeloid cells are indispensable for menopause-associated neuroinflammation and cognitive deficits\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo systematically investigate the structural alterations in the brain during menopause, we established an ovariectomy (OVX) model in adult 9-month-old female mice. Diffusion tensor imaging (DTI) revealed significant changes, with a decrease in fractional anisotropy (FA) values and elevated mean diffusivity (MD) in the cingulate gyrus (CG) and anterior cingulate cortex (ACC) of OVX mice (Fig. 1a\u0026ndash;f). These DTI findings, coupled with the upregulation of inflammatory markers (Il-1\u0026beta;, Ccl2, B2m) in the ACC (Fig. 1g), suggest tissue edema and robust neuroinflammatory responses following ovariectomy. To delineate the contribution of bone marrow-derived myeloid cells, we employed an AAV9 vector expressing GFP under the F4/80 promoter in the bone marrow. Histological analysis revealed a pronounced increase in GFP⁺ cell infiltration into the ACC of OVX mice (Fig. 1h\u0026ndash;i). Critically, myeloid cell depletion using intraosseous clodronate liposomes (Clo) abrogated recognition memory impairment, rescued deficits in cued fear conditioning and spatial learning, and attenuated OVX-induced microglial activation and dendritic spine loss in the ACC (Extended Data Fig. 1a\u0026ndash;j). These results establish myeloid cells as essential mediators of ovariectomy-induced neuroinflammation and associated cognitive decline.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eElevated FSH levels critically drive menopause-associated cognitive decline via myeloid cell-related neuroinflammation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo dissect the direct role of FSH in this process, we employed a gonadotropin-releasing hormone analog (GnRHa) to suppress endogenous gonadotropins\u003csup\u003e13\u003c/sup\u003e, followed by exogenous FSH administration to selectively mimic post-menopausal hypergonadotropism while maintaining stable estradiol levels (Extended Data Fig. S2a\u0026ndash;c). GnRHa treatment rescued memory deficits in NOR, CFC, and MWM tests, a protective effect entirely abolished by exogenous FSH supplementation (Extended Data Fig. S2d\u0026ndash;g). FSH administration also exacerbated microglial activation (Extended Data Fig. S2h\u0026ndash;i). These results reveal that FSH levels play a determinant role in menopause-related cognitive decline. Furthermore, a doxycycline (Dox)-inducible FSH \u0026beta; subunit overexpression model (Fsh\u0026beta;-KI) in ovariectomized, E2-replete mice confirmed that elevated FSH, independent of estrogen fluctuations (Fig. 2a-d), significantly increased the infiltration and proinflammatory activation (CD80⁺, MHC-II⁺) of GFP⁺ myeloid cells in the brain (Fig. 2a\u0026ndash;h). Live imaging dramatically visualized enhanced myeloid cell motility and accumulation in the ACC under high FSH conditions (Fig. 2i\u0026ndash;k; Extended Movies 1\u0026ndash;2). These findings provide compelling evidence that FSH directly promotes the infiltration and proinflammatory activation of myeloid cells in the brain, thereby contributing to neuroinflammation and cognitive impairment in a menopausal context.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMyeloid FSHR signaling restores menopausal neuroinflammation and cognitive impairment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGiven the pivotal role of FSH, we next investigated the therapeutic potential of attenuating myeloid FSH signaling. We generated myeloid-specific FSHR conditional knockout mice (MKO) (Extended Data Fig. 3a), and western blot analysis of purified BMDMs confirmed efficient Fshr knockdown at the protein level (Extended Data Fig. 3b). MKO reversed OVX-induced memory deficits in both NOR and MWM tests (Extended Data Fig. 3c\u0026ndash;d). Mechanistically, MKO mice exhibited significantly reduced infiltration of CD11b⁺Ly6C⁺ monocytes into the brain and lower expression of proinflammatory markers CD86 on brain-resident macrophages (CD45⁺CX3CR1⁺) post-OVX (Extended Data Fig. 3e\u0026ndash;h). Microglial morphology in MKO mice appeared more ramified and homeostatic with showing increased branching endpoints and reduced CD68 expression in MKO mice (Extended Data Fig. 3i\u0026ndash;k). Crucially, MKO preserved dendritic spine density in the ACC following OVX (Extended Data Fig. 3l\u0026ndash;m). These results demonstrate that myeloid FSHR deletion mitigates menopausal cognitive impairment by suppressing neuroinflammation and preserving neuronal structure. Single-cell RNA sequencing (scRNA-seq) on bone marrow CD11b⁺ cells from MKO mice revealed significant compositional shifts and specific gene set enrichment analysis (GSEA) indicated a suppression of inflammatory response and type I interferon signaling in a key macrophage subset (cluster 7) of MKO-OVX mice (Fig. 3a\u0026ndash;g). This striking observation implicated myeloid FSHR in promoting IFN-I signaling.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFSHR signaling in myeloid cells triggers localized IFN-I production and microglial activation in the ACC of menopausal mice\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo validate the connection between myeloid FSHR and IFN-I activation, we found that IFN-\u0026beta; concentration was significantly reduced in the ACC of MKO-OVX mice, accompanied by attenuated IRF3 phosphorylation, without affecting systemic or hippocampal IFN-\u0026beta; levels (Extended Data Fig. 4a\u0026ndash;e). Using an AAV9 vector for F4/80 promoter-driven \u003cem\u003eFshr\u003c/em\u003e shRNA delivery to bone marrow (Fig. 4a\u0026ndash;c), we observed that \u003cem\u003eFshr\u003c/em\u003e knockdown in myeloid cells ameliorated memory deficits and attenuated microglial activation, morphological changes, and local IFN-I protein levels (Fig. 4d\u0026ndash;i; Extended Data Fig. 5a\u0026ndash;d). Spatial analysis confirmed that \u003cem\u003eFshr\u003c/em\u003e knockdown inhibited STAT1 activation in CD68⁺ cells adjacent to GFP⁺ myeloid cells, a clear readout of localized IFN-I signaling (Fig. 4j\u0026ndash;k). Collectively, these findings conclusively establish that FSHR expression in myeloid cells mediates neuroinflammation via localized IFN-I release, which directly contributes to memory impairment in menopausal mice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRestoring NAD\u003c/strong\u003e\u003cstrong\u003e⁺-capped mtRNA ameliorates FSH-driven neuroinflammation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo unravel the molecular underpinnings of FSH-mediated IFN-I induction, multi-omics profiling of Fsh-treated BMDMs revealed enrichment in antiviral immune signaling pathways (Extended Data Fig. 6a\u0026ndash;b) and increased IFN-\u0026beta; secretion, which was abolished by \u003cem\u003eFshr\u003c/em\u003e knockout (Extended Data Fig. 6c). RNase pretreatment and the use of mtDNA/RNA-depleted (\u0026rho;⁰) cells confirmed that cytosolic mtRNA is indispensable for FSH-induced IFN-I pathway activation (Extended Data Fig. 6d\u0026ndash;f).\u003c/p\u003e\n\u003cp\u003eUntargeted metabolomics in FSH-treated BMDMs revealed a dose-dependent decrease in nicotinamide (NAM) and mitochondrial NAD⁺ levels (Fig. 5a\u0026ndash;b). Importantly, FSH reduced NAD⁺-RNA capping, mimicking the effect of NAD⁺ synthesis inhibition FK866 (Fig. 5c; Extended Data Fig. 7a). Exogenous transfection of synthesized NAD⁺-capped mtRNA (NAD\u0026rsquo;-mtRNA) attenuated FSH-induced cytosolic dsRNA accumulation and suppressed IFN-\u0026beta; expression and IFN-I signaling (Fig. 5d; Extended Data Fig. 7b\u0026ndash;e). \u003cem\u003eIn vivo\u003c/em\u003e, local injection of NAD\u0026rsquo;-mtRNA into the ACC of OVX mice downregulated IFN-I expression, suppressed STAT1/IRF3 activation, and reduced microglial activation (Fig. 5g\u0026ndash;l). These results demonstrate that FSH promotes deleterious cytosolic mtRNA leakage and IFN-I activation in myeloid cells, a pathogenic process that can be effectively mitigated by NAD\u0026rsquo;-mtRNA administration, highlighting mtRNA integrity as a novel therapeutic target.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eADARB2 governs mtRNA-triggered IFN-I activation and cognitive deficits in response to FSH\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo identify the mediator of FSH-induced dsRNA production, multi-omics analyses highlighted adenosine deaminase ADARB2 as a top differentially expressed protein (Extended Data Fig. 8a). We found that both siRNA-mediated knockdown and pharmacological inhibition of ADARB2 with 8-Azanebularine (8-Aza), a compound with high binding affinity for ADARB2 (Fig. 6a; Extended Data Fig. 8b), suppressed FSH-induced TBK1/IRF3 phosphorylation and IFN-I expression (Extended Data Fig. 8c\u0026ndash;f). This conclusively links FSH to IFN-I signaling through ADARB2. Mechanistically, RIP-Seq confirmed an interaction between ADARB2 and mtRNA (Extended Data Fig. 9a). Genetic or pharmacological inhibition of ADARB2 increased NAD+-RNA levels, strongly suggesting that ADARB2 negatively regulates NAD⁺ capping (Extended Data Fig. 9b). Overexpression of ADARB2 enhanced cytoplasmic mtRNA and dsRNA accumulation, effects counteracted by NAD\u0026rsquo;-mtRNA supplementation (Extended Data Fig. 9c\u0026ndash;d). These findings unveil a novel regulatory axis where ADARB2, by modulating NAD⁺ capping and subcellular localization of mtRNA, acts as a critical checkpoint for dsRNA-driven innate immune activation.\u003c/p\u003e\n\u003cp\u003eFurthermore, myeloid-specific knockdown of \u003cem\u003eAdarb2\u003c/em\u003e in transplanted BMDMs significantly rescued OVX-induced memory deficits (Extended Data Fig. 10c\u0026ndash;e). Using RFP to track the transplanted BMDMs, we observed that Adarb2 knockdown suppressed microglia adjacent to RFP⁺ donor cells in Ovx mice exhibited classic activation features\u0026mdash;soma enlargement and process retraction (Extended Data Fig. 10g\u0026ndash;i). Adarb2 knockdown decreased STAT1 expression in CD68⁺ cells near RFP⁺ cells (Extended Data Fig. 10j\u0026ndash;k) and elevated BMDMs synaptic density per neuronal (Extended Data Fig. 10l\u0026ndash;m). This provides robust \u003cem\u003ein vivo\u003c/em\u003e evidence that myeloid ADARB2 is a pivotal mediator of cognitive decline in a menopausal model.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePharmacological inhibition of ADARB2 rescues cognitive deficits in menopausal mice\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the potent inhibitory effect of 8-Aza on ADARB2, we conducted a comprehensive pharmacological intervention study (Fig. 6a-b). Systemic administration of 8-Aza profoundly ameliorated menopause-related cognitive and memory deficits across NOR, CFC, and MWM tests (Fig. 6c\u0026ndash;e). At the molecular level, 8-Aza treatment markedly suppressed IFN-I mRNA and protein expression in the ACC, attenuated downstream IFN-I signaling, reduced microglial activation, and enhanced synaptic plasticity (Fig. 6f\u0026ndash;m). Collectively, these results provide compelling evidence that pharmacological inhibition of ADARB2 with 8-Aza is a highly effective strategy for rescuing learning and memory impairments in a menopausal context, strongly supporting its potential as a novel therapeutic strategy.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study uncovers a definitive, previously unidentified pathway linking elevated FSH to neuroinflammation and cognitive decline via myeloid FSHR signaling and aberrant mitochondrial RNA metabolism. Our findings provide a mechanistic explanation for the heightened risk of AD in menopausal women and, crucially, identify several novel and druggable targets, including FSH itself and ADARB2, for the prevention and treatment of menopause-related cognitive disorders.\u003c/p\u003e\n\u003cp\u003eThe markedly higher prevalence of AD in women has largely been attributed to the decline in sex steroid hormones, particularly estrogen, following menopause. However, the molecular mechanisms underlying this sex disparity remain inadequately understood. Our findings fundamentally challenge this estrogen-centric paradigm by positioning elevated FSH as a primary etiological factor. By employing sophisticated mouse models that meticulously dissociate the effects of elevated FSH from other menopausal hormonal changes, specifically the OVX + GnRHa + FSH model and estrogen supplementation in OVX female \u003cem\u003eFshβ\u003c/em\u003e knock-in mice, we provide compelling evidence that FSH itself is a critical and sufficient driver of cognitive impairment, operating independently of estrogen deficiency. This offers a transformative new perspective on the hormonal drivers of postmenopausal brain aging.\u003c/p\u003e\n\u003cp\u003eWhile extra-gonadal FSHR signaling has been implicated in bone metabolism, adiposity, and cholesterol homeostasis\u003csup\u003e14-16\u003c/sup\u003e, its role in the immune system and, critically, the CNS, has been obscure. Our work reveals a pivotal and previously unrecognized function for myeloid FSHR in regulating neuroinflammation. Having established that FSH signaling promotes a pro-inflammatory phenotype in myeloid cells, we elucidated how these peripheral immune cells communicate with the CNS. Bone marrow-derived myeloid cells infiltrate the brain parenchyma and, moreover, FSH signaling through FSHR on these cells is a key promoter of their infiltration and subsequent neuroinflammatory response. The indispensable role of these myeloid cells in mediating menopause-associated cognitive impairment is further underscored by their functional clearance.\u003c/p\u003e\n\u003cp\u003eUpon infiltrating the brain, FSH-primed myeloid cells necessitate an intrinsic mechanism to exacerbate neuroinflammation. Our in-depth investigation into the transcriptomic and metabolic changes within these cells uncovered a surprising and critical role for RNA modification. We propose a novel mechanism whereby NAD⁺ capping of mtRNA serves as a crucial cellular self-surveillance checkpoint, preventing aberrant IFN-I activation.\u0026nbsp;The FSH-mediated reduction in NAD⁺ levels compromise this checkpoint, leading to deleterious cytosolic mtRNA leakage and dsRNA accumulation. This study further elucidates the critical role of ADARB2, an RNA-editing enzyme\u003csup\u003e17\u003c/sup\u003e. In stark contrast to the canonical role of ADAR1 in suppressing interferon responses by editing dsRNA\u003csup\u003e18\u003c/sup\u003e, our findings uniquely position ADARB2 as a positive regulator of neuroinflammation in this context, likely by actively modulating the dynamics of NAD⁺-RNA and dsRNA and potentially engaging MAVS-related signaling\u003csup\u003e19\u003c/sup\u003e. The dramatic amelioration of cognitive deficits upon \u003cem\u003eAdarb2\u003c/em\u003e knockout or pharmacological inhibition unequivocally highlights its pivotal role in this pathogenic pathway and presents a highly promising therapeutic node.\u003c/p\u003e\n\u003cp\u003eIn conclusion, our work definitively uncovers a novel and critical pathway linking elevated FSH to neuroinflammation and cognitive decline via myeloid FSHR signaling and aberrant mtRNA metabolism. This seminal discovery not only provides a robust mechanistic explanation for the heightened risk of AD in menopausal women but, importantly, identifies ADARB2 inhibition and restoration of NAD’-mtRNA integrity as potent, non-estrogenic therapeutic strategies for the prevention and treatment of menopause-related cognitive disorders.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the Key Laboratory of Endocrine Glucose \u0026amp; Lipids Metabolism and Brain Aging (Shandong First Medical University) for consultation and instrument availability that supported this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYL, XZ, WL and DW designed the experiments; RZ, CL, ZR, DW, QX and LZ performed experiments; YL, XZ, XZ and HL interpreted data; YL, DW wrote the manuscript; QX, YL, TL, ZW, ZY and XF provided input on data analysis and computational approaches; HZ, QS, LF, MW and JZ undertook project management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe National Natural Science Foundation of China (No. 82571360, U23A20469, 82130025, 82203819), The Natural Science Foundation of Shandong Province (No. ZR2025MS1433, ZR2023MH322, ZR2024MH290, ZFJH202306), and Shandong Provincial Higher Education Youth Innovation Team Program (No. 2024KJJ017, 2024KJJ025) supported this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData supporting the present study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFisher, D. 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Here, we found that follicle-stimulating hormone (FSH) directly promotes neuroinflammation and cognitive deficits in a mouse model of menopause. We uncover that FSH signaling in myeloid cells triggers the cytosolic leakage of mitochondrial RNA (mtRNA) by reducing NAD+ capping at its 5′ or 3’-end. This aberrant mtRNA accumulation subsequently activates the TBK1–IRF3–IFNβ axis. Critically, the RNA-editing enzyme ADARB2 emerges as a key downstream effector of FSH, governing mtRNA localization and double-stranded RNA (dsRNA) formation. Myeloid-specific deletion of Fshr or Adarb2, or pharmacological inhibition of ADARB2 with 8-Azanebularine, robustly rescues neuroinflammation and cognitive impairment in ovariectomized mice. Furthermore, exogenous administration of NAD+-capped mtRNA attenuates FSH-driven neuroinflammation. Our findings define a pathogenic FSH–FSHR pathway in menopause, challenging estrogen-centric views of brain aging, and identify ADARB2 inhibition and NAD+-mtRNA integrity as potent non-estrogenic therapeutic strategies for menopause-associated cognitive decline.","manuscriptTitle":"Myeloid FSH-FSHR signaling drives menopause-associated cognitive decline via a mitochondrial RNA-dependent neuroinflammation axis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-09 10:46:15","doi":"10.21203/rs.3.rs-8773348/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":"adc11d1f-0bbd-4550-9f0a-aa7fc95aac05","owner":[],"postedDate":"February 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":62336493,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases"},{"id":62336494,"name":"Health sciences/Neurology/Neurological disorders"}],"tags":[],"updatedAt":"2026-03-06T16:20:15+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-09 10:46:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8773348","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8773348","identity":"rs-8773348","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}