BACE Inhibition as a Therapeutic Strategy for Alzheimer`s Disease

Alzheimer`s disease (AD) is the most common age-related neurodegenerative disease and the most common cause of dementia. One of the characteristic hallmarks of AD brains upon post-mortem examination is the presence of amyloid plaques containing aggregates of the neurotoxic amyloid-β peptide Aβ. This peptide is produced from the amyloid precursor protein (APP) by proteolytic cleavage, firstly by BACE1 (β-site amyloid precursor protein cleaving enzyme 1 or β-secretase) and subsequently by γ-secretase. After Phase III, clinical trials of a α γ-secretase inhibitor were abandoned due to adverse secondary effects, the focus has shifted to BACE1 as a key drug target in AD. Numerous BACE inhibitors have been produced, many of which have been shown in animal models to reduce the levels of Aβ in the brain. Intensive research effort for more than a decade has seen certain BACE1 inhibitors advance through human trials. Despite this progress, however, concerns that using BACE1 inhibition to reduce Aβ could cause unwanted side effects (termed “mechanism-based toxicity”) that have arisen as the list of BACE1 substrates continues to grow. In addition to APP, recent proteomics studies have identified novel BACE1 substrates, many of which have known roles in the developing and mature brain. This chapter aims to review the BACE inhibition strategy and describe the development of BACE inhibitors for AD therapy, highlighting both the promise and the potential pitfalls of this approach. The potential consequences of inhibiting BACE1 processing of these other BACE1 substrates along with APP will be discussed.

Keywords: Alzheimer`s disease, amyloid-β peptide, Aβ, β-site amyloid precursor protein cleaving enzyme 1, β-secretase, BACE1, drug, inhibitor, mechanismbased toxicity, substrates, Type I transmembrane proteins, Sez6 protein family.