BACE1: Biological Functions and Involvement in the Pathophysiology of Alzheimer's Disease and Other Neurological Disorders

β-Secretase (BACE1) is the key enzyme responsible for generating Amyloid-β (Aβ) peptides, whose aggregation and plaque formation are major hallmarks of Alzheimer's disease (AD). Owing to its central role in Aβ production, BACE1 has become a widely studied therapeutic target in the search for disease-modifying treatments for AD. However, evidence of numerous physiological substrates indicates that BACE1 participates in diverse biological processes, from the development and maintenance of the nervous system through control of neuronal differentiation and axonal myelination to immune response mediation by promotion of cell-cell interactions. These functions prompted research into the enzyme's role in Other neurodegenerative disorders such as Parkinson's disease, Niemann-Pick type C disease, and Creutzfeldt-Jakob disease, whose pathophysiology includes aberrant protein aggregation and/or cognitive decline leading to dementia as seen in AD, as well as in neurological conditions such as schizophrenia and epilepsy, which are characterized by impaired neurotransmission and seizures, respectively. This review summarizes current knowledge on BACE1 substrates involved in nervous system regulation and immune response, highlights its roles at the molecular and genetic levels across aforementioned disorders, and outlines outcomes from clinical trials of BACE1 inhibitors.

aspartyl protease; clinical trials; inhibition; sheddase protein; substrate promiscuity; transmembrane proteins.