BACE2, also known as β -site APP cleavage enzyme 2, is a protease that plays crucial roles in multiple biological processes. It is involved in the proteolytic processing of the amyloid precursor protein (APP) and is initially proposed as an alternative β -secretase to BACE1. However, accumulating evidence shows it acts as a non-amyloidogenic α -secretase, preventing the generation of Aβ42 peptides, thus having a neuroprotective role in Alzheimer's disease (AD) [1,2]. BACE2 is also highly expressed in cerebrovascular endothelium and may function as a vascular protective protein [3]. Additionally, it has been implicated in diabetes as a Collectrin (TMEM27) secretase controlling pancreatic β -cell proliferation [4].

In AD-related studies, BACE2 deficiency in human brain microvascular endothelial cells (BMECs) using small interfering RNA significantly decreased the expression of endothelial nitric oxide synthase (eNOS) and reduced nitric oxide production [3]. In hPSC-derived brain organoids, the BACE2 loss-of-function mutation (BACE2G446R) led to greater apoptosis and increased levels of Aβ oligomers, resembling AD-associated phenotypes [6]. In giant pandas, a homozygous 25-bp deletion in the first exon of Bace2 may cause brown-and-white coat color by reducing the number and size of melanosomes [5].

In conclusion, BACE2 is a multi-functional protease. Its role in AD-associated pathology, cerebrovascular endothelial function, and even coat color determination in giant pandas has been revealed through various functional studies, including gene knockout-like experiments in cell models and animals. Understanding BACE2 functions provides new insights for developing therapeutic strategies for AD and other related diseases.

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. Southan, Christopher. 2013. BACE2 as a new diabetes target: a patent review (2010 - 2012). In Expert opinion on therapeutic patents, 23, 649-63. doi:10.1517/13543776.2013.780032. https://pubmed.ncbi.nlm.nih.gov/23506624/

5. Guan, Dengfeng, Sun, Shuyan, Song, Lingyun, Hu, Yibo, Wei, Fuwen. 2024. Taking a color photo: A homozygous 25-bp deletion in Bace2 may cause brown-and-white coat color in giant pandas. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2317430121. doi:10.1073/pnas.2317430121. https://pubmed.ncbi.nlm.nih.gov/38437540/

6. 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/