Bace1, also known as beta-site amyloid precursor protein (APP)-cleaving enzyme 1 or β-secretase, is an aspartic protease. It is crucial as it initiates the production of amyloid-β peptide (Aβ) through the proteolytic cleavage of APP, a process involved in the amyloidogenic pathway. This pathway is closely associated with the pathophysiology of Alzheimer's disease (AD), making Bace1 a prime drug target for reducing Aβ levels in early AD [2,3,4].

Numerous Bace1 inhibitors have been developed for AD treatment, but most clinical trials were discontinued due to safety or efficacy issues. Bace1 also has substrates important for synaptic plasticity and homeostasis, and cross-inhibition of other aspartic proteases like BACE2 contributed to adverse side effects [3]. Additionally, recent studies indicate Bace1 is involved in metabolic, vascular, and immune functions, playing a role in aging, diabetes, hypertension, and cancer, suggesting new 'druggable' targets against aging comorbidities [1].

In conclusion, Bace1 is essential in the amyloidogenic pathway related to AD. Its role extends to other physiological functions and diseases. Mouse models, especially KO/CKO mouse models, could potentially help in further understanding its functions in these disease conditions. The failed clinical trials of Bace1 inhibitors for AD highlight the complexity of targeting Bace1, while new findings on its role in other diseases open up new research directions [1,2,3].

References:

1. Bao, Hong, Shen, Yong. 2022. Unmasking BACE1 in aging and age-related diseases. In Trends in molecular medicine, 29, 99-111. doi:10.1016/j.molmed.2022.11.008. https://pubmed.ncbi.nlm.nih.gov/36509631/

2. Patel, Smith, Bansoad, Ankush Vardhaman, Singh, Rakesh, Khatik, Gopal L. . BACE1: A Key Regulator in Alzheimer's Disease Progression and Current Development of its Inhibitors. In Current neuropharmacology, 20, 1174-1193. doi:10.2174/1570159X19666211201094031. https://pubmed.ncbi.nlm.nih.gov/34852746/

3. Coimbra, Judite R M, Resende, Rosa, Custódio, José B A, Salvador, Jorge A R, Santos, Armanda E. . BACE1 Inhibitors for Alzheimer's Disease: Current Challenges and Future Perspectives. In Journal of Alzheimer's disease : JAD, 101, S53-S78. doi:10.3233/JAD-240146. https://pubmed.ncbi.nlm.nih.gov/38943390/

4. Sathya, M, Premkumar, P, Karthick, C, Jayachandran, K S, Anusuyadevi, M. 2012. BACE1 in Alzheimer's disease. In Clinica chimica acta; international journal of clinical chemistry, 414, 171-8. doi:10.1016/j.cca.2012.08.013. https://pubmed.ncbi.nlm.nih.gov/22926063/