Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E.
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.
Barger
S W
SW
Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock 72205, USA. swbarger@life.uams.edu
Harmon
A D
AD
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D007375:Interleukin-1; D016328:NF-kappa B; D010446:Peptide Fragments; D019001:Nitric Oxide Synthase