BACE1

BACE1 (β-site APP-cleaving enzyme 1) is a type I transmembrane aspartyl protease that initiates amyloid precursor protein (APP) processing by cleaving APP at the β-secretase site, thereby generating the N-terminus of amyloid-β (Aβ) peptides and promoting subsequent γ-secretase-dependent Aβ production^[1][2]. BACE1 localizes predominantly to acidic intracellular compartments, including endosomes and the trans-Golgi network, where its catalytic activity supports amyloidogenic APP processing and contributes directly to Alzheimer’s disease (AD)-associated amyloid pathology^[1][3]. Mechanistically, genetic and biochemical studies demonstrate that BACE1 is the principal β-secretase in the central nervous system, and BACE1 deficiency markedly reduces cerebral Aβ generation, amyloid deposition, and Aβ-associated cognitive impairments in experimental AD models^[3]. Beyond APP processing, BACE1 cleaves multiple neuronal membrane proteins involved in axon guidance, synaptic function, neurogenesis, and myelination, indicating broader physiological roles in nervous system development and maintenance^[3]. Compared with the closely related isoform BACE2, which preferentially cleaves APP within the Aβ domain and thereby limits Aβ formation, BACE1 functions as the dominant amyloidogenic β-secretase in neurons and remains the primary therapeutic target for reducing pathological Aβ production^[3]. Therefore, selective BACE1 inhibitors have been extensively developed as experimental and clinical tools to suppress Aβ generation, although long-term inhibition requires consideration of BACE1-dependent physiological pathways and substrate processing functions^[3][4].