Scientists unveil potential Alzheimer’s disease drug target

March 15th, 2008 - 1:18 pm ICT by admin  

Washington, March 15 (ANI): A study on mice conducted by researchers at the University of California, San Diego, has revealed a way whereby the overproduction of a peptide associated with Alzheimers disease can be reduced.

We discovered two chemical compounds that inhibit a new enzyme target, leading to reduced production of beta-amyloid and improved memory in a mouse model of Alzheimers disease, said Dr. Vivian Y. H. Hook, professor of neurosciences, pharmacology and medicine at the UCSD School of Medicine.

The accumulation of amyloid plaque deposits, composed primarily of the neurotoxic beta-amyloid (Aa) peptide, is a hallmark sign of Alzheimers disease.

One drug strategy to fight the disease is to reduce the production of Aa peptides, which develop when a type of protein called protease enzymes cut a larger protein called amyloid precursor protein (APP).

The protease must cut the APP amino acid sequence in two places at the beta-secretase and the gamma-secretase sites to generate Aa peptides.

In the current study, the researchers prevented the protease from cutting the APP chain into smaller peptides, which led to an improved memory and reduced levels of beta-amyloid protein in the brains of mice that had been bred to exhibit Alzheimers disease symptoms.

Dr. Hook said that past research had shown that a mutant beta-secretase sequence, also known as Swedish mutant sequence, result in the overproduction of Aa peptides, and that a protease called BACE1 could cut this mutant sequence.

In the present study, the research team has found that a different protease called Cathepsin B (CatB) works to cut the normal beta-secretase site which is present in more than 99 per cent of Alzheimers cases but not the Swedish mutant site.

The researchers also tested compounds that inhibit CatB E64d and CA074Me in a mouse model of Alzheimers disease with the normal beta-secretase site.

After drug treatment, using water maze memory tests, we found that the mice exhibited great improvement in their memory, as well as reduced brain levels of beta amyloid. These results are consistent with previous research indicating that CatB is elevated in brains of patients with Alzheimers disease, said Dr. Hook.

Based on their observations, the researchers came to the conclusion that a drug that targets CatB in humans could be an effective treatment for Alzheimers disease in the more than 99 per cent of individuals with the normal beta-secretase site.

By disabling the enzymes ability to cut the beta end of the amino acid sequence, researchers may discover a way to limit production of neurotoxic Aa and reduce amyloid plaques in the brain, said Dr. Hook.

The study has been described in a paper published in the online edition of the Journal of Biological Chemistry. (ANI)

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