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

Sepideh Kiani Shabestari, Samuel Morabito, Emma Pascal Danhash, Amanda Mcquade, Jessica Ramirez Sanchez, Emily Miyoshi, Jean Paul Chadarevian, Christel Claes, Morgan Alexandra Coburn, Jonathan Hasselmann, Jorge Hidalgo, Kayla Nhi Tran, Alessandra C. Martini, Winston Chang Rothermich, Jesse Pascual, Elizabeth Head, David A. Hume, Clare Pridans, Hayk Davtyan, Vivek SwarupMathew Blurton-jones

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)110961
JournalCell Reports
Volume39
Issue number11
DOIs
Publication statusPublished - 14 Jun 2022

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