Drugs Modulate Protein Important in Alzheimer's

Affect pathogenic peptide production and aggregation

WEDNESDAY, June 18 (HealthDay News) -- Some non-steroidal anti-inflammatory drugs can bind to the amyloid-β protein, affecting the production of a pathogenic peptide and inhibiting its aggregation, which may be useful in reducing the deposition of amyloid-β in patients with Alzheimer's disease, researchers report in the June 12 issue of Nature.

Thomas L. Kukar, Ph.D., from the Mayo Clinic College of Medicine in Jacksonville, Fla., and colleagues developed tagged, photoactivatable versions of small-molecule γ-secretase modulators (fenofibrate and flurbiprofen-benzophenone) to identify their cellular targets.

The researchers found that the compounds bound to β-amyloid precursor protein and its carboxy-terminal fragments, as well as amyloid-β peptide, but not the core proteins of the γ-secretase complex. The interaction took place via amino acids 28-36 of amyloid-β, a region important for aggregation, and mutation of this site in the β-amyloid precursor protein affected its sensitivity to these compounds.

"These findings indicate that substrate targeting by γ-secretase modulators mechanistically links two therapeutic actions: alteration in Aβ42 production and inhibition of amyloid-β aggregation, which may synergistically reduce amyloid-β deposition in Alzheimer's disease," Kukar and colleagues conclude.

Abstract
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