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Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model

ABSTRACT: This dataset allows for the exploration of microglial function on gene expression in wild-type and the 5xFAD mouse model of Alzheimer's disease, across multiple brain regions. Mice were treated with the selective CSF1R inhibitor PLX5622, which eliminates >95% of microglia in less than 5 days, from 1.5 to 7 months of age. Thus, these data allow the exploration of the effects, and specificity, of 6 months microglial depletion, in both wild-type and 5xFAD mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE134151 | GEO | 2019/07/12

REPOSITORIES: GEO

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single-cell RNA-seq profile of adult microglia under acute Csf1r inhibition and early repopulation

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single-cell RNA-seq profile of microglia under acute Csf1r inhibition and early repopulation in adult brain

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Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model

Project description:Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model

| PRJNA554106 | ENA

Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model.

Project description: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, A? 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.

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CSF1R inhibition by PLX5622 affects multiple immune cell compartments with tissue-specific metabolic effects

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