Function, regulation and therapeutic properties of beta-secretase (BACE1).
beta-Secretase (beta-site amyloid precursor protein cleaving enzyme 1; BACE1) has been identified as the rate limiting enzyme for amyloid-beta-peptide (Abeta) production. Abeta is the major component of amyloid plaques and vascular deposits in Alzheimer's disease (AD) brains and believed to initiate the deadly amyloid cascade. BACE1 is the principle beta-secretase, since its knock-out completely prevents Abeta generation. BACE1 is likely to process a number of different substrates and consequently several independent physiological functions may be exerted by BACE1. Currently the function of BACE1 in myelination is best understood. BACE1 cleaves and activates Neuregulin-1 and is thus directly involved in myelination of the peripheral nervous system during early postnatal development. However, additional physiological functions specifically within the central nervous system are so far less understood. BACE1 is upregulated in at least some AD brains. Multiple cellular mechanisms for BACE1 regulation are known including post-transcriptional regulation via its 5'-untranslated region, microRNA and non-coding anti-sense RNA. BACE1 is a primary target for Abeta lowering therapies, however the development of high affinity bio-available inhibitors has been a major challenge so far.
Willem
Michael
M
Center for Integrated Protein Science Munich, Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig-Maximilians-University, 80336 Munich, Germany. mwillem@med.uni-muenchen.de
Lammich
Sven
S
Haass
Christian
C
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D011499:Protein Processing, Post-Translational
D016229:Amyloid beta-Peptides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human