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Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice

2022; Cell Press; Volume: 39; Issue: 11 Linguagem: Inglês

10.1016/j.celrep.2022.110961

2639-1856

Sepideh Kiani Shabestari, Samuel Morabito, Emma Danhash, Amanda McQuade, Jessica Sanchez, Emily Miyoshi, Jean Paul Chadarevian, Christel Claes, Morgan Coburn, Jonathan Hasselmann, Jorge Luis Silva Hidalgo, Kayla Nhi Tran, Alessandra Cadete Martini, Winston Chang Rothermich, Jesse R. Pascual, Elizabeth Head, David Hume, Clare Pridans, Hayk Davtyan, Vivek Swarup, Mathew Blurton‐Jones,

Tryptophan and brain disorders

Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2.