Proteolytic mechanisms in amyloid-β metabolism: therapeutic implications for Alzheimerʹs disease

The accumulation of the amyloid-β peptide, the main constituent of the ‘amyloid plaque’, is widely considered to be the key pathological event in Alzheimerʹs disease. Amyloid-β is produced from the amyloid precursor protein through the action of the proteases β-secretase and γ-secretase. Alternative cleavage of amyloid precursor protein by the enzyme α-secretase precludes amyloid-β production. In addition, several proteases are involved in the degradation of amyloid-β. This review focuses on the proteolytic mechanisms of amyloid-β metabolism. An increasingly detailed understanding of proteolysis in both amyloid-β deposition and clearance has identified some of these proteases as potential therapeutic targets for Alzheimerʹs disease. A more complex knowledge of these proteases takes us one step closer to developing ‘diseasemodifying’ therapies, but these advances also emphasize that significant challenges must be overcome before clinically effective drugs to treat Alzheimerʹs disease become a reality.