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

A role for β-amyloid precursor protein (β-APP) in the development of Alzheimer's disease has been indicated by genetics1, and many conditions in which β-APP is raised have been associated with an increased risk of Alzheimer's disease or an Alzheimer's-like pathology2,3,4. Inflammatory events may also contribute to Alzheimer's disease5. Here we investigate whether a secreted derivative of β-APP (sAPP-α) can induce inflammatory reactions in microglia, which are brain cells of monocytic lineage. We found that treatment with sAPP-α increased markers of activation in microglia and enhanced their production of neurotoxins. The ability of sAPP-α 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's6. A product of amyloidogenic β-APP processing (sAPP-β) also activated microglia. Because sAPP-β is deficient in the neuroprotective activity shown by sAPP-α, our results indicate that increased amyloidogenic processing could adversely affect the balance of sAPP activities that determine neuronal viability.