The most popular current hypothesis is that Alzheimer’s disease (AD) is caused by aggregates of the amyloid peptide (Aβ), which is generated by cleavage of the Aβ protein precursor (APP) by β-secretase (BACE-1) followed by γ-secretase. BACE-1 is a type-I integral membrane glycoprotein with a 21-residue cleavable signal sequence, a large ectodomain of ~434 aa, a single transmembrane domain of ~22 aa and a short cytoplasmic tail of 24 residues. Several post-translational modifications have been reported on BACE-1, including phosphorylation of a serine in the cytoplasmic domain, palmitoylation of three cysteines in the transmembrane/cytoplasmic domain, sulfation of the N-linked oligosaccharides and inclusion of four glycosylation sites in the catalytic domain. BACE-1 cleavage is limiting for the production of Aβ, making it a particularly good drug target for the generation of inhibitors that lower Aβ.  
APP is processed by β-secretase to produce Aβ, BACE-1 cleaves APP at the expected sites on its extracellular domains at positions D1 and E11. When cells were transfected with APP lacking the transmembrane domain, they were not cleaved by BACE-1, suggesting that the enzyme is a membrane bound protease, and only cleaves APP when membrane bound.BACE-1 accepts a wide variety of substrates, preferring acidic or polar residues in contrast to other known aspartyl proteases.  NF-kB acts as a repressor for BACE-1 transcription in differentiated neuronal cultures and nonactivated glial cultures, but as an activator for BACE-1 in activated astrocytic and Aβ-exposed neuronal cultures. Depletion of PPARγ results in an increase in the levels of the BACE-1 promoter, wherein mutation at PPRE increases the promoter activity. CD147 is a component of the γ secretase complex, and hence the complex may modulate BACE-1 expression. BACE-1 expression was increased in cells stimulated with the M1/M3-selective muscarinic ACh receptor agonist talsaclidine. Protein kinase C activation by phorbol esters led to up regulation of BACE-1.


1.Chitra Venugopal,et al. CNS Neurol Disord Drug Targets. 2008 Jun; 7(3): 278–294.