β-Amyloid peptides and amyloid plaques in Alzheimer's disease

Abstract

Many lines of evidence support that β-amyloid (Aβ) peptides play an important role in Alzheimer's disease (AD), the most common cause of dementia. But despite much effort the molecular mechanisms of how Aβ contributes to AD remain unclear. While Aβ is generated from its precursor protein throughout life, the peptide is best known as the main component of amyloid plaques, the neuropathological hallmark of AD. Reduction in Aβ has been the major target of recent experimental therapies against AD. Unfortunately, human clinical trials targeting Aβ have not shown the hoped-for benefits. Thus, doubts have been growing about the role of Aβ as a therapeutic target. Here we review evidence supporting the involvement of Aβ in AD, highlight the importance of differentiating between various forms of Aβ, and suggest that a better understanding of Aβ's precise pathophysiological role in the disease is important for correctly targeting it for potential future therapy.

Fig. 1

A schema of amyloid precursor protein (APP) with its major cleavage sites and familial Alzheimer’s disease (AD) mutations mentioned in the text. Depicted are the amyloidgenic pathway of APP, cleavage sites on the Aβ peptide, and the Arctic and Osaka familial AD mutations. Although other mutations in β-amyloid (Aβ)/APP are not shown, it is important to note that all mutations in APP linked to familial AD are either within Aβ or at the β- or γ-cleavage sites. In the amyloidgenic pathway APP is cleaved by β-secretase to generate C-terminal fragment β (βCTF) and then further cleaved by γ-secretase to generate Aβ. In the nonamyloidgenic pathway, Aβ production is precluded as it is cleaved in the middle by α-secretase. AICD = APP intracellular domain