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

Elizabeth Spangenberg, Paul L. Severson, Lindsay A. Hohsfield, Joshua Crapser, Jiazhong Zhang, Elizabeth A. Burton, Ying Zhang, Wayne Spevak, Jack Lin, Nicole Y. Phan, Gaston Habets, Andrey Rymar, Garson Tsang, Jason Walters, Marika Nespi, Parmveer Singh, Stephanie Broome, Prabha Ibrahim, Chao Zhang, Gideon Bollag, Brian L. West and Kim N. Green ()
Additional contact information
Elizabeth Spangenberg: University of California Irvine (UCI)
Paul L. Severson: Plexxikon Inc
Lindsay A. Hohsfield: University of California Irvine (UCI)
Joshua Crapser: University of California Irvine (UCI)
Jiazhong Zhang: Plexxikon Inc
Elizabeth A. Burton: Plexxikon Inc
Ying Zhang: Plexxikon Inc
Wayne Spevak: Plexxikon Inc
Jack Lin: Plexxikon Inc
Nicole Y. Phan: University of California Irvine (UCI)
Gaston Habets: Plexxikon Inc
Andrey Rymar: Plexxikon Inc
Garson Tsang: Plexxikon Inc
Jason Walters: Plexxikon Inc
Marika Nespi: Plexxikon Inc
Parmveer Singh: Plexxikon Inc
Stephanie Broome: Plexxikon Inc
Prabha Ibrahim: Plexxikon Inc
Chao Zhang: Plexxikon Inc
Gideon Bollag: Plexxikon Inc
Brian L. West: Plexxikon Inc
Kim N. Green: University of California Irvine (UCI)

Nature Communications, 2019, vol. 10, issue 1, 1-21

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11674-z

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