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

By Elizabeth E. Spangenberg, P. Severson, Lindsay A. Hohsfield, Joshua D. Crapser, Jiazhong Zhang, Elizabeth A. Burton, Ying Zhang, W. Spevak, Jacki Lin, Nicole Y. Phan and 12 more. Nature Communications, 2019

721 citations recorded by the source corpus.

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. Genetics implicate microglia in Alzheimer’s disease pathogenesis, but their roles remain unclear. Here, the authors find that microglial depletion in a mouse model of Alzheimer’s disease impairs plaque formation and that Aβ-induced changes in neuronal gene expression are microglia-mediated.

Subfields: Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/3e694fe2e99a78fdb9cd33e218acd99a93cc12a0

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Neurology

1. J. Long
2. D. Holtzman

In Physiology

1. J. Long
2. D. Holtzman
3. Berislav Zlokovic

Citations in the corpus

• Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, positive): “In support of a role for microglia in exacerbating amyloid pathology, a recent study using pharmacological depletion of microglia in amyloid mice during the period of plaque deposition demonstrated reduced parenchymal plaques following robust microglial depletion (Spangenberg et al., 2019).”