Figure 5.

Hypothetical model of hAPP effects in AD. In aging brain, neurons are exposed to increasing oxidative stress and other injurious factors that could trigger the p53 pathway and cause neuronal degeneration. Wild-type hAPP helps prevent p53 activation, whereas FAD-mutant hAPP or hAPP variants resulting from “molecular misreading” in sporadic AD (56, 57) may be deficient in or counteract this function. Increased production of Aβ42 in FAD (8, 54) and unknown factors in sporadic AD promote Aβ aggregation, resulting in a vicious pathogenetic cycle that could sensitize neurons to other insults and promote neurodegeneration. For clarity, the diagram focuses on hAPP and p53; additional pathways are likely to contribute to AD pathogenesis.