Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer's-like disease progression

Nat Commun. 2013;4:2030. doi: 10.1038/ncomms3030.

Abstract

In Alzheimer's disease, soluble amyloid-β causes synaptic dysfunction and neuronal loss. Receptors involved in clearance of soluble amyloid-β are not known. Here we use short hairpin RNA screening and identify the scavenger receptor Scara1 as a receptor for soluble amyloid-β expressed on myeloid cells. To determine the role of Scara1 in clearance of soluble amyloid-β in vivo, we cross Scara1 null mice with PS1-APP mice, a mouse model of Alzheimer's disease, and generate PS1-APP-Scara1-deficient mice. Scara1 deficiency markedly accelerates Aβ accumulation, leading to increased mortality. In contrast, pharmacological upregulation of Scara1 expression on mononuclear phagocytes increases Aβ clearance. This approach is a potential treatment strategy for Alzheimer's disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • CD36 Antigens / metabolism
  • Cysteine Endopeptidases / pharmacology
  • Disease Progression*
  • Drug Combinations
  • HEK293 Cells
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism*
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Microglia / drug effects
  • Microglia / metabolism
  • Phagocytes / drug effects
  • Phagocytes / metabolism*
  • Presenilin-1 / metabolism
  • Proteolysis / drug effects
  • RNA, Small Interfering / metabolism
  • Scavenger Receptors, Class A / deficiency*
  • Scavenger Receptors, Class A / metabolism
  • Solubility
  • Survival Analysis
  • Up-Regulation / drug effects

Substances

  • Amyloid beta-Peptides
  • CD36 Antigens
  • Drug Combinations
  • Lipopolysaccharides
  • Msr1 protein, mouse
  • Presenilin-1
  • Protollin
  • RNA, Small Interfering
  • Scavenger Receptors, Class A
  • Cysteine Endopeptidases