Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E

Nature. 1997 Aug 28;388(6645):878-81. doi: 10.1038/42257.


A role for beta-amyloid precursor protein (beta-APP) in the development of Alzheimer's disease has been indicated by genetics, and many conditions in which beta-APP is raised have been associated with an increased risk of Alzheimer's disease or an Alzheimer's-like pathology. Inflammatory events may also contribute to Alzheimer's disease. Here we investigate whether a secreted derivative of beta-APP (sAPP-alpha) can induce inflammatory reactions in microglia, which are brain cells of monocytic lineage. We found that treatment with sAPP-alpha increased markers of activation in microglia and enhanced their production of neurotoxins. The ability of sAPP-alpha to activate microglia was blocked by prior incubation of the protein with apolipoprotein E3 but not apolipoprotein E4, a variant associated with an increased risk for Alzheimer's. A product of amyloidogenic beta-APP processing (sAPP-beta) also activated microglia. Because sAPP-beta is deficient in the neuroprotective activity shown by sAPP-alpha, our results indicate that increased amyloidogenic processing could adversely affect the balance of sAPP activities that determine neuronal viability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Apolipoproteins E / metabolism*
  • Cell Death
  • Cell Line
  • Gene Expression Regulation
  • Humans
  • Inflammation / metabolism
  • Interleukin-1 / biosynthesis
  • Interleukin-1 / genetics
  • Microglia / cytology
  • Microglia / metabolism*
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase / genetics
  • Peptide Fragments / metabolism*
  • Rats


  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Apolipoproteins E
  • Interleukin-1
  • NF-kappa B
  • Peptide Fragments
  • Nitric Oxide Synthase