The all-out assault to impede production of b-amyloid (Ab), the plaque-forming peptide believed by many to cause neurodegenerative Alzheimer's disease (AD), entails a war on two fronts. For those aiming to prevent plaques at their cellular source, the two clear targets are b-secretase and g-secretase, which sequentially cleave amyloid precursor protein (APP) to generate Ab. Some victories are emerging: Small molecules designed to inhibit g-secretase activity are being clinically tested, and the 1999 identification and cloning of b-secretase led researchers to design small molecule inhibitors.

Courtesy of John Q. Trojanowski

Guilty by Association: While researchers are not yet certain of the causative agent in Alzheimer's, insoluble peptides like Ab aggregate outside the neural cells to form amyloid plaques associated with the disease.

g-secretase, which has made it farthest as a drug target, still has an identity problem. One camp...

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