Betasecretase

Beta-secretase, commonly referred to as beta-site APP-cleaving enzyme, is a class of proteases that initiates the amyloidogenic processing of the amyloid precursor protein (APP). The principal human enzyme is BACE1 (beta-site APP-cleaving enzyme 1), a type I transmembrane aspartyl protease. A closely related homolog, BACE2, exists with distinct tissue distribution and substrate preferences. The term betasecretase is often used to describe these enzymes collectively.

BACE1 operates in the secretory and endocytic pathways, in an acidic cellular environment such as the Golgi and endosomes. Its catalytic mechanism relies on a pair of aspartate residues in the active site, forming a catalytic dyad that cleaves APP at the beta site. This cleavage releases soluble APPβ (sAPPβ) and leaves a membrane-bound C99 fragment. Subsequent processing by gamma-secretase generates amyloid-beta (Aβ) peptides, which can aggregate and are associated with Alzheimer's disease pathology. BACE1 also cleaves a variety of other substrates, including neuregulin-1 and certain cell adhesion molecules, contributing to roles in myelination, synaptic function, and development.

Physiologically, BACE1 supports multiple processes beyond APP processing. BACE2 shares homology but its brain involvement in APP metabolism is less clear, and it may have distinct roles in other tissues such as the pancreas. In mouse models, loss of BACE1 disrupts myelination and neural development, highlighting its broad physiological importance.

Therapeutically, beta-secretase inhibitors (BACE inhibitors) have been pursued as disease-modifying treatments for Alzheimer's disease. Although these inhibitors can lower Aβ production, clinical trials have encountered safety concerns and limited cognitive benefit, and no BACE inhibitor is currently approved. Research continues into selective inhibition strategies and alternate approaches to modulate the APP processing pathway.