Drug-Like Compounds Break Down Alzheimer's Protein

Amyloid β-protein abnormally accumulates in the brain in patients with Alzheimer's disease

01 may 2009-- Two small molecules can promote the breakdown of amyloid β-protein, which accumulates in the brain in patients with Alzheimer's disease and is implicated in disease pathogenesis, according to a report published online April 22 in PLoS ONE.

Christelle Cabrol, from the Mayo Clinic in Jacksonville, Fla., and colleagues performed high-throughput screening in the presence and absence of adenosine triphosphate (ATP) using a library of about 32,000 compounds to identify small molecules that would activate insulin-degrading enzyme (IDE), an enzyme that breaks down the amyloid β-protein.

The researchers identified two compounds, Ia1 and Ia2, that significantly stimulated the proteolytic activity of IDE. Both compounds bound in the ATP-binding site of the enzyme. Ia1 activated the degradation of amyloid β-protein by about 700 percent, while Ia2 activated degradation by about 400 percent, according to the study.

"This study describes the first examples of synthetic small-molecule activators of IDE, showing that pharmacological activation of this important protease with drug-like compounds is achievable," Cabrol and colleagues conclude.

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