BACE2, also known as β -site APP cleavage enzyme 2, is a protease involved in the proteolytic processing of the amyloid precursor protein (APP) [1,2]. Unlike BACE1, it cleaves APP within the Aβ domain, preventing the generation of Aβ42 peptides, thus playing a non-amyloidogenic role and having potential as a therapeutic target for Alzheimer's disease (AD) [1]. It is also involved in cerebrovascular endothelium-related functions, potentially acting as a vascular protective protein [2,3].

Genetic downregulation of BACE2 with small interfering RNA in human brain microvascular endothelial cells decreased the expression of endothelial nitric oxide synthase (eNOS) and nitric oxide production, and suppressed APP expression and soluble APPα production [3]. In BACE2-deficient mice, endothelium-dependent relaxations to acetylcholine and basal production of cyclic GMP were impaired in cerebral arteries [3]. In hPSC-derived brain organoids, BACE2 loss-of-function mutation led to greater apoptosis and increased Aβ oligomers, resembling AD-associated phenotypes [4].

In conclusion, BACE2 plays a crucial role in preventing Aβ42 peptide generation and has protective functions in cerebrovascular endothelium. Gene-knockout models, such as BACE2-deficient mice and hPSC-derived brain organoids with BACE2 loss-of-function mutations, have revealed its role in AD-related pathological processes and cerebrovascular function, providing insights for the development of AD therapies and understanding of cerebrovascular protection mechanisms.

References:

1. Yeap, Yee Jie, Kandiah, Nagaendran, Nizetic, Dean, Lim, Kah-Leong. . BACE2: A Promising Neuroprotective Candidate for Alzheimer's Disease. In Journal of Alzheimer's disease : JAD, 94, S159-S171. doi:10.3233/JAD-220867. https://pubmed.ncbi.nlm.nih.gov/36463454/

2. Sáez-Valero, Javier, Pérez-González, Rocío. 2023. BACE2 beyond β-processing of APP, its neuroprotective role in cerebrovascular endothelium. In Journal of neurochemistry, 166, 887-890. doi:10.1111/jnc.15940. https://pubmed.ncbi.nlm.nih.gov/37587672/

3. He, Tongrong, d'Uscio, Livius V, Katusic, Zvonimir S. 2023. BACE2 deficiency impairs expression and function of endothelial nitric oxide synthase in brain endothelial cells. In Journal of neurochemistry, 166, 928-942. doi:10.1111/jnc.15929. https://pubmed.ncbi.nlm.nih.gov/37547981/

4. Luo, Juan, Zou, Hailin, Guo, Yibo, Ngan, Elly Sau-Wai, Li, Peng. 2022. BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids. In Cell death discovery, 8, 47. doi:10.1038/s41420-022-00845-5. https://pubmed.ncbi.nlm.nih.gov/35110536/