Signaling effect of amyloid-beta(42) on the processing of AbetaPP.

The effects of amyloid-beta are extremely complex. Current work in the field of Alzheimer disease is focusing on discerning the impact between the physiological signaling effects of soluble low molecular weight amyloid-beta species and the more global cellular damage that could derive from highly concentrated and/or aggregated amyloid. Being able to dissect the specific signaling events, to understand how soluble amyloid-beta induces its own production by up-regulating BACE1 expression, could lead to new tools to interrupt the distinctive feedback cycle with potential therapeutic consequences. Here we describe a positive loop that exists between the secretases that are responsible for the generation of the amyloid-beta component of Alzheimer disease. According to our hypothesis, in familial Alzheimer disease, the primary overproduction of amyloid-beta can induce BACE1 transcription and drive a further increase of amyloid-beta precursor protein processing and resultant amyloid-beta production. In sporadic Alzheimer disease, many factors, among them oxidative stress and inflammation, with consequent induction of presenilins and BACE1, would activate a loop and proceed with the generation of amyloid-beta and its signaling role onto BACE1 transcription. This concept of a signaling effect by and feedback on the amyloid-beta precursor protein will likely shed light on how amyloid-beta generation, oxidative stress, and secretase functions are intimately related in sporadic Alzheimer disease.