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.
Tabaton
Massimo
M
Departments of Neuroscience, Ophthalmology, and Genetics, University of Genova, Genova, Italy. mtabaton@neurologia.unige.it
Zhu
Xiongwei
X
Perry
George
G
Smith
Mark A
MA
Giliberto
Luca
L
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D010446:Peptide Fragments / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human