Inhibition of beta-amyloid formation as a therapeutic strategy

A considerable body of evidence has accumulated in recent years implicating the beta-amyloid protein (A beta) in the aetiology of Alzheimer's disease (AD). The highly hydrophobic A beta can nucleate and form neurotoxic fibril s which are characteristic components of AD neuritic plaques. Three general strategies for preventing or slowing the A beta-initiated cascade of event s leading to AD are (1) block the downstream signalling pathways that resul t in cytotoxic responses to A beta fibrils, (2) interfere with A beta nucle ation and fibrillogenesis, and (3) inhibit the proteolytic events that lead to A beta generation. In this article, we provide a perspective on the cur rent knowledge of the molecular basis of AD, discuss the advantages of the third therapeutic strategy, blocking A beta production, and review the a re cent journal and patent literature describing compounds that work at this l evel. Finally, we will discuss the most pressing issues that need to be add ressed in order to more effectively develop useful therapeutic agents that lower A beta concentrations in the central nervous system (CNS).