Bace2, short for β -site APP cleavage enzyme 2, is a protease that plays a crucial role in the proteolytic processing of the amyloid precursor protein (APP). Unlike BACE1, BACE2 cleaves APP within the Aβ domain, preventing the generation of Aβ42 peptides and thus having a non-amyloidogenic role. This places it as a potential therapeutic target in Alzheimer's disease (AD) [1]. It is also involved in the regulation of endothelial nitric oxide synthase (eNOS) function in cerebrovascular endothelium, suggesting a vascular protective role [2,3].

Genetic downregulation of Bace2 with small interfering RNA in human brain microvascular endothelial cells decreased eNOS expression and nitric oxide production, while Bace2-deficient mice showed impaired endothelium-dependent relaxations to acetylcholine and basal cyclic GMP production, indicating its importance in maintaining normal cerebrovascular function [3]. In human pluripotent stem cell-derived brain organoids, a Bace2 loss-of-function mutation led to increased apoptosis and Aβ oligomers, resembling AD-associated phenotypes [4].

In conclusion, Bace2 has a non-amyloidogenic role in APP processing and is crucial for maintaining normal cerebrovascular function. Studies using gene-knockout models, such as the genetic downregulation in cells and Bace2-deficient mice, have revealed its significance in AD-related pathological processes and cerebrovascular health, providing potential directions for therapeutic development in these disease areas.