BACE1

BACE1, or beta-site amyloid precursor protein cleaving enzyme 1, is a human gene encoding an aspartyl protease that initiates the amyloidogenic processing of the amyloid precursor protein (APP). The enzyme is a type I transmembrane glycoprotein that traffics through the secretory pathway to the Golgi and endosomes, where acidic conditions optimize its proteolytic activity.

BACE1 belongs to the aspartic protease family and uses two catalytic aspartate residues to cleave APP at the beta site. Its main physiological function is to generate the soluble ectodomain sAPPβ and the membrane-bound C99 fragment, the latter of which is further cleaved by γ-secretase to release amyloid-beta peptides that can aggregate in Alzheimer's disease. BACE1 also cleaves a variety of other substrates, including neuregulin-1 type III and various receptors, and these broader substrates contribute to its roles in neural development, synaptic function, and possibly myelination.

Clinically, BACE1 is a central target in efforts to reduce amyloid-beta production in Alzheimer's disease. BACE1 expression is elevated in some AD brains and in response to cellular stress. Inhibitors of BACE1 were developed as disease-modifying therapies, but several compounds failed in late-stage trials due to safety concerns and lack of clear cognitive benefit, highlighting challenges in achieving effective and tolerable suppression of BACE1 activity. Research continues to refine selectivity, brain penetration, and safety or to pursue partial inhibition strategies.

In animal models, BACE1 knockout mice show markedly reduced Aβ production but exhibit phenotypes related to impaired myelination and synaptic function, underscoring the enzyme’s broader roles in the nervous system.