REGULATION OF APPMETABOLISM BY PROTEIN PHOSPHORYLATION

A hallmark of Alzheimer disease (AD) is the build-up of an amyloid protein (AP) (Glenner and Wong, 1984, Masters et aI., 1985) in the brain parenchyma and in the cerebrovasculature (Tomlinson and Corsellis, 1984). AP is derived from a large transmembrane precursor, the amyloid protein precursor (APP) (Goldgaber et aI., 1987, Kang et aI., 1987, Kitaguchi et aI., 1988, Ponte et aI., 1988, Robakis et aI., 1987, Tanzi et aI., 1987, Tanzi et aI., 1988). For a variety of reasons, many researchers believe that the build-up of AP in the brain causes the synaptic loss and associated dementia which occurs in AD. These reasons include the observation that one of the several mutations (hereafter referred to as the Swedish mutation, Mullan et aI., 1992) in APP which cosegregate with AD is associated with abnormally high production of AP (Cai et aI., 1993, Citron et aI., 1992). It therefore seems plausible to argue that increased production of AI3 might underlie the symptoms of AD in individuals bearing this mutation. More recently it has been shown that an allele ofapolipoprotein E (ApoE(4» is associated with forms of AD (Corder et aI., 1993, Strittmatter et aI., 1993). This allele of ApoE is especially prone to inducing the aggregation and precipitation of AP in vitro. In the case of individuals with ApoE(4) it is possible that there is an associated increase in AI3 deposition (Schmechel et aI., 1993) which again might underlie the symptoms of AD. Thus, there is evidence to suggest that both increased AI3 production and decreased AP clearance may contribute to AD. From