Recent advances in Alzheimer's disease therapy: clinical trials and literature review of novel enzyme inhibitors targeting amyloid precursor protein.

Introduction: Amyloid precursor protein (APP) plays a central role in the pathophysiology of Alzheimer's disease (AD). The accumulation of beta-amyloid protein is believed to be a crucial step in the development of AD. Therefore, understanding the complex biology of APP and its various cleavage products may be useful for developing effective therapeutic strategies for AD.

Areas covered: The amyloidogenic pathway of APP processing involves proteolytic cleavage by two prominent secretases, γ-Secretase and β-secretase. In the late 2000s, multiple pharmaceutical drugs that inhibited γ-Secretase and β-Secretase were synthesized, some of which advanced to human clinical trials. Unfortunately, neither γ-Secretase nor β-secretase inhibitors have been approved by the FDA due to both lack of efficacy and concerns for serious side effects.

Expert opinion: While targeting of Aβ accumulation through secretase inhibitors was halted due to severe side effects, γ-Secretase modulators (GSMs) have arisen as a potential alternative approach. First-generation GSMs could modulate γ-secretase activity without affecting Notch cleavage. However, to improve potency and brain penetration, second-generation GSMs were developed to reduce levels of the amylogenic form of Aβ, Aβ42, without affecting the NOTCH signaling pathway. Several of these drugs have progressed to clinical trials, although with mixed results. The development of GSM's continues to serve as a potentially safer approach to modulating Aβ production in AD treatment.