Transcriptional and post-transcriptional regulation of ß-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-beta-peptides (A beta). A beta results from two sequential endoproteolytic cleavages operated on the amyloid-beta precursor protein (A beta PP), an integral membrane protein with a single-membrane spanning domain, a large extracellular N-terminus and a shorter, cytoplasmic C-terminus. First, beta-secretase (BACE1) cleaves A beta PP at the N-terminal end of the A beta sequence to produce a secreted form of A beta PP, named sA beta PP, and a C-terminal membrane-bound 99-aminoacid fragment (C99). Then, ?-secretase cleaves C99 within the transmembrane domain to release the A beta peptides of different lengths, predominantly A beta 1-40 and A beta 1-42. (C) 2012 IUBMB IUBMB Life, 64(12): 943950, 2012