β- and γ-secretases as therapeutic targets for Alzheimer's disease

Abstract

Alzheimer's disease (AD) continues to be a major global health concern, affecting more than 55 million people worldwide. While there have been notable advancements in understanding the pathogenesis of AD, the trigger and intricate mechanisms involved in disease progression remain elusive. According to the amyloid hypothesis, which continues to be the most dominant hypothesis, the deposition of β-amyloid protein (Aβ) aggregates initiates a cascade of events that ultimately lead to neuronal dysfunction and dementia. Nonamyloidogenic processing of amyloid precursor protein (APP) requires an initial cut by α-secretase followed by a second cut by γ-secretase to release soluble extracellular p3 peptide. However, in amyloidogenic processing, APP is first cut by β-secretase (BACE1, β-site APP-cleaving enzyme 1), followed by further cleavage by γ-secretase to release Aβ peptide into extracellular space that ultimately leads to the amyloid formation and plaques. Thus, targeting either inhibiting BACE-1 or modulating the activity of γ-secretase has become an attractive target for AD drug discovery programs. Extensive research has been carried out in designing inhibitors of BACE-1 and γ-secretase to modulate Aβ production and reduce its aggregation. These inhibitors target the active sites of the secretases, blocking their enzymatic activity and ultimately reducing Aβ levels. However, BACE-1 is a membrane protein, and γ-secretase is a membrane protein complex, which makes it difficult to target their active sites. In addition, a successful drug candidate for AD must meet specific requirements for central nervous system (CNS) penetration. This necessitates careful consideration of the structure–activity relationship and other physicochemical aspects while developing anti-AD pharmacological agents.