Transcriptional and post‐transcriptional regulation of β‐secretase

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that results in loss of memory and cognitive function, eventually leading to dementia. A key neuropathological event in AD is the cerebral accumulation of senile plaques formed by aggregates of amyloid‐β‐peptides (Aβ). Aβ results from two sequential endoproteolytic cleavages operated on the amyloid‐β precursor protein (AβPP), an integral membrane protein with a single‐membrane spanning domain, a large extracellular N‐terminus and a shorter, cytoplasmic C‐terminus. First, β‐secretase (BACE1) cleaves AβPP at the N‐terminal end of the Aβ sequence to produce a secreted form of AβPP, named sAβPP, and a C‐terminal membrane‐bound 99‐aminoacid fragment (C99). Then, γ‐secretase cleaves C99 within the transmembrane domain to release the Aβ peptides of different lengths, predominantly Aβ1‐40 and Aβ1‐42. © 2012 IUBMB IUBMB Life, 64(12): 943–950, 2012