The role of BACE1 in Alzheimer's disease and its suitability as a therapeutic target

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment, loss of neuronal cells and synaptic connections. The main pathological feature of the disease is the ? amyloid peptide, generated by the cleavage of the Amyloid Precursor Protein by the ?-secretase enzyme (Beta-site APP-cleaving enzyme 1 (BACE1)). There have been many factors involved in the increase in BACE1 gene expression and activity, including energy inhibition, hypoxia and increased cholesterol. The biological function of BACE1 makes it a perfect target for therapeutic treatment of AD and although BACE1 inhibitors have been in development for over a decade, most of them have undesirable features. Currently several pharmaceutical companies have BACE1 inhibitors in different stages of clinical trials but there are still issues like the lack of selectivity for BACE1 over BACE2 and the possible consequences of BACE1 inhibition on other BACE1 substrates.