BACE2

BACE2 (β-site APP-cleaving enzyme 2) is a type I transmembrane aspartyl protease that belongs to the β-secretase family and shares substantial sequence homology with BACE1, yet displays distinct substrate selectivity and physiological functions.^[1][2] Mechanistically, BACE2 predominantly cleaves amyloid precursor protein (APP) within the Aβ region through θ-secretase-like activity, thereby reducing amyloidogenic processing and limiting Aβ generation in multiple experimental systems.^[1][3][4] Beyond APP metabolism, BACE2 regulates ectodomain shedding of physiologically relevant substrates, including VEGFR3, and modulates lymphangiogenic VEGFR3 signaling by controlling receptor abundance and soluble VEGFR3 release.^[2] In disease-associated contexts, BACE2 has been linked to Alzheimer’s disease, Down syndrome-related amyloid pathology, and age-dependent alterations in APP processing, where substrate conformation and cellular environment influence its proteolytic activity.^[3][4][5] Compared with the closely related isoform BACE1, which functions as the principal β-secretase responsible for amyloidogenic APP cleavage, BACE2 generally exhibits anti-amyloidogenic activity and possesses distinct tissue distribution and substrate preferences.^[1][2][4] Experimental studies further demonstrate that BACE2-mediated cleavage of TMEM27, PMEL, VEGFR3, and additional membrane proteins contributes to the regulation of glucose homeostasis, pigmentation, lymphatic signaling, and protein shedding pathways.^[1][2] For research applications, selective discrimination between BACE1 and BACE2 activity remains essential during inhibitor development, as dual inhibition may alter physiological BACE2-dependent signaling and confound interpretation of therapeutic responses.^[1][2]