Another Target For Alzheimer's Drugs

With a molecular probe inspired by a leukemia medication, researchers have discovered a new protein target for drugs to treat Alzheimer’s disease (Nature 2010, 467, 95). Blocking the activity of the target, called γ-secretase-activating protein, might stop accumulation of the neurotoxic peptide amyloid-β and slow progression of the brain disease. Blocking enzymes that make amyloid-β has been challenging. One such enzyme, the protease γ-secretase, slices several important proteins besides the precursor to amyloid-β. Drugmakers take pains to design γ-secretase inhibitors that interfere only with amyloid-β, but it isn’t clear how γ-secretase distinguishes among its different substrates in nature. Rockefeller University’s Paul Greengard and colleagues thought the secret might lie with Gleevec, a leukemia drug that only inhibits γ-secretase’s ability to make amyloid-β. So they developed a light-activated, radiolabeled Gleevec probe to unravel the basis for the selectivity. They uncovered γ-secretase-activating protein, which they learned binds to γ-secretase and a precursor of amyloid-β to direct γ-secretase’s activity. Lowering levels of the activating protein reduced amyloid-β levels in a mouse with Alzheimer’s, so the team is optimistic that inhibitors of the activating protein might be successful against Alzheimer’s in humans.