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

Sepideh Kiani Shabestari(University of California, Irvine), Samuel Morabito(University of California, Irvine), Emma Danhash(University of California, Irvine), Amanda McQuade(University of California, Irvine), Jessica Sanchez(University of California, Irvine), Emily Miyoshi(University of California, Irvine), Jean Paul Chadarevian(University of California, Irvine), Christel Claes(University of California, Irvine), Morgan Coburn(University of California, Irvine), Jonathan Hasselmann(University of California, Irvine), Jorge Luis Silva Hidalgo(University of California, Irvine), Kayla Nhi Tran(University of California, Irvine), Alessandra Cadete Martini(University of California, Irvine), Winston Chang Rothermich(University of California, Irvine), Jesse R. Pascual(University of California, Irvine), Elizabeth Head(University of California, Irvine), David Hume(The University of Queensland), Clare Pridans(Centre for Inflammation Research), Hayk Davtyan(University of California, Irvine), Vivek Swarup(University of California, Irvine), Mathew Blurton‐Jones(University of California, Irvine)
Cell Reports
June 1, 2022
10.1016/j.celrep.2022.110961
Cited by 180Open Access
Full Text

Abstract

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.

Related Papers

No related papers found

Powered by citation graph analysis