Proteolytic mechanisms in amyloid-β metabolism:: therapeutic implications for Alzheimer's disease

The accumulation of the amyloid-beta peptide, the main constituent of the 'amyloid plaque', is widely considered to be the key pathological event in Alzheimer's disease. Amyloid-beta is produced from the amylold precursor protein through the action of the proteases beta-secretase and gamma-secretase. Alternative cleavage of amyloid precursor protein by the enzyme a-secretase precludes amyloid-beta production. In addition, several proteases are involved in the degradation of amyloid-beta. This review focuses on the proteolytic mechanisms of amyloid-beta metabolism. An increasingly detailed understanding of proteolysis in both amyloid-beta deposition and clearance has identified some of these proteases as potential therapeutic targets for Alzheimer's 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 Alzheimer's disease become a reality.