Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques

Nat Commun. 2015 Jan 29:6:6176. doi: 10.1038/ncomms7176.

Abstract

In Alzheimer's disease (AD), β-amyloid (Aβ) plaques are tightly enveloped by microglia processes, but the significance of this phenomenon is unknown. Here we show that microglia constitute a barrier with profound impact on plaque composition and toxicity. Using high-resolution confocal and in vivo two-photon imaging in AD mouse models, we demonstrate that this barrier prevents outward plaque expansion and leads to compact plaque microregions with low Aβ42 affinity. Areas uncovered by microglia are less compact but have high Aβ42 affinity, leading to the formation of protofibrillar Aβ42 hotspots that are associated with more severe axonal dystrophy. In ageing, microglia coverage is reduced leading to enlarged protofibrillar Aβ42 hotspots and more severe neuritic dystrophy. CX3CR1 gene deletion or anti-Aβ immunotherapy causes expansion of microglia coverage and reduced neuritic dystrophy. Failure of the microglia barrier and the accumulation of neurotoxic protofibrillar Aβ hotspots may constitute novel therapeutic and clinical imaging targets for AD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging
  • Amyloid / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Brain / drug effects
  • Brain / pathology
  • CX3C Chemokine Receptor 1
  • Coloring Agents / metabolism
  • Diffusion
  • Female
  • Gene Deletion
  • Humans
  • Immunization
  • Male
  • Mice
  • Microglia / drug effects
  • Microglia / metabolism*
  • Microglia / pathology
  • Neurites / drug effects
  • Neurites / metabolism
  • Neuroprotective Agents / pharmacology
  • Neurotoxins / metabolism*
  • Peptide Fragments / metabolism*
  • Plaque, Amyloid / metabolism*
  • Receptors, Chemokine / metabolism
  • Solubility
  • Staining and Labeling

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • CX3C Chemokine Receptor 1
  • Coloring Agents
  • Cx3cr1 protein, mouse
  • Neuroprotective Agents
  • Neurotoxins
  • Peptide Fragments
  • Receptors, Chemokine
  • amyloid beta-protein (1-42)