Beta-secretase 2 (BACE2) (BACE2)

Beta-secretase 2 (BACE2) is a transmembrane aspartic protease and a close homolog of BACE1, the primary enzyme responsible for the generation of amyloid-beta (Aβ) peptides in Alzheimer's disease (UniProt Consortium, 2023). While BACE1 is predominantly expressed in the brain, BACE2 is expressed in various peripheral tissues and at lower levels in the brain (Bennett et al., 2000). BACE2 plays a critical role in the processing of several substrates, including the pigment cell-specific protein PMEL, which is essential for melanosome formation, and Tmem27, which regulates pancreatic beta-cell mass (Rochin et al., 2013; Esterházy et al., 2011). In the context of Alzheimer's disease, BACE2 can cleave the amyloid precursor protein (APP) at the theta-site, a process that actually prevents the formation of toxic Aβ species (Sun et al., 2006). However, many small-molecule BACE inhibitors developed for Alzheimer's disease lack selectivity and inhibit both BACE1 and BACE2. This dual inhibition has led to clinical safety concerns, most notably skin and hair hypopigmentation due to the disruption of PMEL processing (Shimshek et al., 2016).

Other names

Aspartic protease 1Asp 1Memapsin-1Beta-site amyloid precursor protein cleaving enzyme 2Down region aspartic proteaseCEAP1

Inhibition of aspartic protease activity to prevent substrate cleavage