Absence of microglia promotes diverse pathologies andearly lethality in Alzheimer's disease mice

Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet the precise mechanisms underlying their effects on neuropathology remain unclear. To further define the influence of microglia on AD neuropathology, we generated a novel mouse model of AD that genetically lack microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA) that is further accompanied by transcriptional changes within multiple cell types, a dramatic induction of brain calcification and cerebral hemorrhages, and premature lethality. Importantly, adult microglia replacement fully rescues these comorbidities, supporting novel roles for microglia in maintaining vascular function and preventing brain calcification. We further examined the clinical implications of these findings in human tissue and hiPSC-derived microglia, finding evidence that calcification is inversely related to plaque pathology and that microglial interactions with calcifications are altered by genetic AD risk factors. Overall design: An unbiased survey of the cellular landscape in genetic microglia loss in Alzheimer's Disease mice (5XFAD)