Inhibition of β-amyloid formation as a therapeutic strategy

Abstract

A considerable body of evidence has accumulated in recent years implicating the β-amyloid protein (Aβ) in the aetiology of Alzheimer’s disease (AD). The highly hydrophobic Aβ can nucleate and form neurotoxic fibrils which are characteristic components of AD neuritic plaques. Three general strategies for preventing or slowing the Aβ-initiated cascade of events leading to AD are (1) block the downstream signalling pathways that result in cytotoxic responses to Aβ fibrils, (2) interfere with Aβ nucleation and fibrillogenesis, and (3) inhibit the proteolytic events that lead to Aβ generation. In this article, we provide a perspective on the current knowledge of the molecular basis of AD, discuss the advantages of the third therapeutic strategy, blocking Aβ production, and review the recent journal and patent literature describing compounds that work at this level. Finally, we will discuss the most pressing issues that need to be addressed in order to more effectively develop useful therapeutic agents that lower Aβ concentrations in the central nervous system (CNS).