Aspirin-triggered Lipoxin A4 Stimulates Alternative Activation of Microglia and Reduces Alzheimer Disease-Like Pathology in Mice

Am J Pathol. 2013 May;182(5):1780-9. doi: 10.1016/j.ajpath.2013.01.051. Epub 2013 Mar 16.

Abstract

Microglia play an essential role in innate immunity, homeostasis, and neurotropic support in the central nervous system. In Alzheimer disease (AD), these cells may affect disease progression by modulating the buildup of β-amyloid (Aβ) or releasing proinflammatory cytokines and neurotoxic substances. Discovering agents capable of increasing Aβ uptake by phagocytic cells is of potential therapeutic interest for AD. Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory properties directly involved in inflammatory resolution, an active process essential for appropriate host responses, tissue protection, and the return to homeostasis. Herein, we demonstrate that aspirin-triggered LXA4 (15 μg/kg) s.c., twice a day, reduced NF-κB activation and levels of proinflammatory cytokines and chemokines, as well as increased levels of anti-inflammatory IL-10 and transforming growth factor-β. Such changes in the cerebral milieu resulted in recruitment of microglia in an alternative phenotype, as characterized by the up-regulation of YM1 and arginase-1 and the down-regulation of inducible nitric oxide synthase expression. Microglia in an alternative phenotype-positive cells demonstrated improved phagocytic function, promoting clearance of Aβ deposits and ultimately leading to reduction in synaptotoxicity and improvement in cognition. Our data indicate that activating LXA4 signaling may represent a novel therapeutic approach for AD.

Publication types

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

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology*
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aspirin / pharmacology
  • Aspirin / therapeutic use*
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Cognition / drug effects
  • Lipoxins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Microglia / metabolism*
  • Microglia / pathology*
  • NF-kappa B / metabolism
  • Neuroprotective Agents / pharmacology
  • Phenotype
  • Protein Processing, Post-Translational / drug effects
  • Synapses / drug effects

Substances

  • Amyloid beta-Peptides
  • Lipoxins
  • NF-kappa B
  • Neuroprotective Agents
  • lipoxin A4
  • Aspirin