Integrated Stress Response Associated with Dark Microglia Contributes to Neurodegeneration
44 Pages Posted: 18 Apr 2024 Publication Status: Accepted
More...Abstract
Microglia, the brain’s primary resident immune cells, can assume various phenotypes with diverse functional outcomes on brain homeostasis. In Alzheimer’s disease (AD), where microglia are a leading causal cell type, the identity of microglia subsets that drive neurodegeneration remains unresolved. Here, we identify a microglia phenotype characterized by a conserved stress signaling pathway, the integrated stress response (ISR). Using mouse models to activate or inhibit ISR in microglia, we show that ISR underlies the ultrastructurally distinct “dark” microglia subset linked to pathological synapse loss. Inducing microglial ISR in murine AD models exacerbates neurodegenerative pathologies, such as Tau pathology and synaptic terminal loss. Conversely, inhibiting microglial ISR in AD models ameliorates these pathologies. Mechanistically, we present evidence that ISR promotes the secretion of toxic long- chain lipids that impair neuron and oligodendrocyte homeostasis in vitro. Accordingly, inhibition of lipid synthesis in AD models ameliorates synaptic terminal loss. Our results demonstrate that activation of ISR within microglia represents a pathway contributing to neurodegeneration and suggest that this may be sustained, at least in part, by the secretion of long-chain lipids from ISR-activated microglia.
Note:
Funding Information: This work was supported by the CUNY Research Foundation, Alzheimer’s Association AARG- 22-974642 (P.A.), Alfred P. Sloan Foundation JFRASE (P.A.), Provost’s Pre-Dissertation Science Research Fellowships (A.F., L.A.), CIHR Foundation FDN341846 (M.-E.T.), Tier II CRC in Neurobiology of Aging and Cognition CRC-2019-00407 (M.-E.T.), CFI John R. Evans Leaders Fund 39965 (M.-E.T.), National Multiple Sclerosis Society Grant TA-1905-34048 (S.W.), NIH R01 MH131219 (N.J.H), as well as generous support by Robin Chemers Neustein.
Conflict of Interests: The authors declare no competing interests.
Ethical Approval: The brain bank at CERVO Brain Research Center (QC, Canada) and handling of the post-mortem human tissues were approved by the Ethics Committee of the University of Victoria, Institut Universitaire en Santé Mentale de Québec, and Université Laval. Written consent was obtained for using post-mortem tissues, and all analyses were performed per the Code of Ethics of the World Medical Association. All animal protocols were approved by IACUC at CUNY Advanced Science Research Center CMU and performed according to NIH guidelines.
Keywords: microglia, neurodegeneration, integrated stress response, ISR, dark microglia, Alzheimer's Disease, non-cell-autonomous signaling
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