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

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…

• UD
  U.S. Department of Energy

  Awards: -AC02-05CH11231, 05CH11231, AC02-05CH11231, DE-AC02, DE-AC02-05CH11231, DE-AC02-
• AA
  Alzheimer's Association

  Award: AARF-16-442762
• NI
  National Institutes of Health

  Awards: R01AG056768, P50AG016573, DE-AC02-05CH11231, R01NS083801
• OO
  Office of Science

  Awards: AC02-05CH11231, -AC02-05CH11231, DE-AC02
• NI
  National Institute on Aging

  Awards: R01AG056768, F31AG059367, T32AG00096, P50AG016573
• NI
  National Institute of Neurological Disorders and Stroke

  Awards: R01NS083801, R01AG056768