Abstract
Many risk genes for the development of Alzheimer’s disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aβ deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis.
Highlights
Many risk genes for the development of Alzheimer’s disease (AD) are exclusively or highly expressed in myeloid cells
To investigate the potential for microglia-mediated plaque formation, we examined Aβ aggregates within microglia in transgenic mouse models of AD
Microglia are critically dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival[17], and we set out to develop specific CSF1R inhibitors that were orally bioavailable, brain-penetrant, and able to achieve robust brainwide microglia elimination for extended periods of time
Summary
Many risk genes for the development of Alzheimer’s disease (AD) are exclusively or highly expressed in myeloid cells. Alzheimer’s disease (AD) is a progressive, age-related neurodegenerative disorder thought to be triggered by the appearance and build-up of amyloid-β (Aβ) plaques in the cortex[1,2] These plaques subsequently spread throughout the forebrain and lead to a cascade of events, culminating in synaptic and neuronal loss that underlie the disease-associated memory impairments. With the elimination of microglia, we uncovered critical roles of these cells in plaque formation, compaction, and growth, mitigating neuritic dystrophy, and modulating hippocampal neuronal gene expression in response to Aβ pathology. These results implicate microglia as critical and causative in the development and progression of multiple facets of AD pathology
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