BACE2 (beta-secretase 2) is an aspartic protease that plays a neuroprotective role by cleaving amyloid precursor protein (APP) within the amyloid-β domain, thereby preventing the generation of toxic Aβ42 peptides that drive Alzheimer's disease pathogenesis 1. Unlike its homolog BACE1, BACE2 functions as a non-amyloidogenic α-secretase that reduces Aβ production through cleavage downstream of the α-secretase site 2. In Down syndrome patients with trisomy 21, the extra copy of BACE2 acts as a dose-sensitive AD suppressor gene, with organoid studies showing that BACE2 elimination triggers AD-like pathology 1. BACE2 generates protective Aβ-preventing fragments (Aβ1-19) and degradation products (Aβ1-20, Aβ1-34) in both organoid models and cerebrospinal fluid of DS patients 1. Beyond APP processing, BACE2 cleaves vascular endothelial growth factor receptor 3 (VEGFR3), modulating lymphangiogenic signaling and serving as a biomarker for BACE2 activity 3. The enzyme also preserves cerebrovascular endothelial nitric oxide synthase function, contributing to vascular protection 4. These neuroprotective functions position BACE2 as a promising therapeutic target for Alzheimer's disease, contrasting with the pathogenic role of BACE1 5.