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 Swarup,
Mathew Blurton-Jones
Affiliations
Sepideh Kiani Shabestari
Department of Neurobiology & Behavior, UC Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA
Samuel Morabito
Mathematical, Computational and System Biology (MCSB) Program, UC Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA 92697, USA
Emma Pascal Danhash
Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA
Amanda McQuade
Department of Neurobiology & Behavior, UC Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA 92697, USA
Jessica Ramirez Sanchez
Department of Neurobiology & Behavior, UC Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA
Emily Miyoshi
Department of Neurobiology & Behavior, UC Irvine, Irvine, CA 92697, USA
Jean Paul Chadarevian
Department of Neurobiology & Behavior, UC Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA
Christel Claes
Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA 92697, USA
Morgan Alexandra Coburn
Department of Neurobiology & Behavior, UC Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA
Jonathan Hasselmann
Department of Neurobiology & Behavior, UC Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA
Jorge Hidalgo
Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA
Kayla Nhi Tran
Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA
Alessandra C. Martini
Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA 92697, USA; Department of Pathology & Laboratory Medicine, UC Irvine, Irvine, CA 92697, USA
Winston Chang Rothermich
Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA
Jesse Pascual
Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA 92697, USA; Department of Pathology & Laboratory Medicine, UC Irvine, Irvine, CA 92697, USA
Elizabeth Head
Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA 92697, USA; Department of Pathology & Laboratory Medicine, UC Irvine, Irvine, CA 92697, USA
David A. Hume
Mater Research Institute-University of Queensland, Brisbane, Australia
Clare Pridans
University of Edinburgh Centre for Inflammation Research, Edinburgh, UK; Simons Initiative for the Developing Brain Centre, University of Edinburgh, Edinburgh, UK; The Muir Maxwell Epilepsy Centre, University of Edinburgh, Edinburgh, UK
Hayk Davtyan
Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA 92697, USA
Vivek Swarup
Department of Neurobiology & Behavior, UC Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA 92697, USA
Mathew Blurton-Jones
Department of Neurobiology & Behavior, UC Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA 92697, USA; Corresponding author
Summary: 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.
