Mechanism mediating oligomeric Aβ clearance by naïve primary microglia

Neurobiol Dis. 2011 Jun;42(3):221-30. doi: 10.1016/j.nbd.2011.01.005. Epub 2011 Jan 8.

Abstract

The accumulation of soluble oligomeric amyloid-β peptide (oAβ) proceeds the formation of senile plaques and contributes to synaptic and memory deficits in Alzheimer's disease (AD). The mechanism of mediating microglial oAβ clearance remains unclear and thought to occur via scavenger receptors (SRs) in microglia. SRs respond to their ligands in a subtype-specific manner. Therefore, we sought to identify the specific subtypes of SRs that mediate oAβ internalization and proteases that degrade oAβ species in naïve primary microglia. The component of oAβ species were characterized by western blot analysis, analytical ultracentrifugation analysis, and atomic force microscopy. The oAβ species remained soluble in the medium and microglial lysates during incubation at 37 °C. SR-A, but not CD36, mediated oAβ internalization in microglia as suggested by the use of subtype-specific neutralizing antibodies and small interfering RNAs (siRNAs). Immunoprecipitation analysis showed that oAβ interacted with SR-A on the plasma membrane. After internalization, over 40% of oAβ vesicles were trafficked toward lysosomes and degraded by cysteine proteases, including cathepsin B. The inhibitors of proteasome, neprilysin, matrix metalloproteinases, and insulin degrading enzyme failed to protect internalized oAβ from degradation. Our study suggests that SR-A and lysosomal cathepsin B are critical in microglial oAβ clearance, providing insight into how microglia are involved in the clearance of oAβ and their roles in the early stages of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Immunohistochemistry
  • Insulysin / metabolism
  • Lysosomes / metabolism
  • Mice
  • Microglia / metabolism*
  • Neprilysin / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Scavenger / metabolism*

Substances

  • Amyloid beta-Peptides
  • RNA, Small Interfering
  • Receptors, Scavenger
  • Neprilysin
  • Insulysin
  • Proteasome Endopeptidase Complex