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- W4312088047 abstract "Background Microglia and other resident macrophages in the central nervous system (CNS) exhibit heterogeneous phenotypes dependent on spatiotemporal context, allowing them to fulfil various functions in health and disease. Emerging data suggest that microglia mediate synaptic loss in Alzheimer’s disease (AD) (Bartels et al., Science 2020), yet we know little about the underlying mechanisms and potential subsets or cell states involved. Method We performed single-molecule fluorescent hybridisation (smFISH) using RNAScope, immunohistochemistry, super-resolution microscopy, ultrastructural microscopy (CLEM), flow cytometry, and a newly generated SPP1-reporter mouse to identify cellular source of SPP1 in the hippocampus of mice. We assessed SPP1 mRNA and protein, as well as synapse and complement pathology in hAPP-NL-F knock-in mice. We validated localisation of SPP1 in AD human patient brains. To assess functional effects of SPP1 in the hippocampus, we performed intracerebroventricular injections of oligomeric Abeta in wild-type (WT) vs. SPP1 KO mice. Result Here we report SPP1/Osteopontin, a glycoprotein involved in phagocytosis, is upregulated in a region-specific manner in the hippocampus of AD mouse and human brains. There is a brain-region specific upregulation of SPP1 mRNA and protein in hippocampus of AD models, coinciding at a time point of complement deposition and when synapses are vulnerable to microglial engulfment. Interestingly, we found that SPP1 is produced not by microglia but by a type of CNS-resident macrophages that line the perivascular space, i.e., the perivascular macrophages (PVM), which is then secreted to alter microglial engulfment state. In Spp1-knockout mice, Aβ oligomers are unable to induce synapse loss as compared to wild-type controls. Furthermore, microglia fail to upregulate phagocytic markers as well as C1q. Conclusion Our data suggest SPP1 and PVM as mediators of synapse engulfment in pre-plaque AD mouse models" @default.
- W4312088047 created "2023-01-04" @default.
- W4312088047 creator A5077912766 @default.
- W4312088047 date "2022-12-01" @default.
- W4312088047 modified "2023-10-16" @default.
- W4312088047 title "Perivascular SPP1 modulates microglia‐synapse engulfment in Alzheimer’s disease models." @default.
- W4312088047 doi "https://doi.org/10.1002/alz.061895" @default.
- W4312088047 hasPublicationYear "2022" @default.
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