Protease Inhibitors Reduce Amyloid Plaque Formation in Mouse Model of Alzheimer's Disease

Neuroscientists have found that inhibitors of the proteolytic enzyme cathepsin B prevented formation of toxic beta-amyloid (A-beta) peptides and amyloid plaque deposits in the brains of the animals in a mouse model of Alzheimer's disease.

Two sequential cleavages of the amyloid precursor protein (APP) are required for generation of the 40 or 42 amino acid-long amyloid-â peptides that aggregate in the brain of Alzheimer's patients. Beta-secretase (BACE) is a membrane-bound aspartyl protease that cleaves the amyloid precursor protein to generate the N-terminus of the A-beta peptide. BACE has been implicated to be an excellent target for anti-amyloid therapy for the treatment of Alzheimer's disease. Finding BACE inhibitors is one of the major goals of Alzheimer's disease drug development.

In the current study, investigators at the University of California, San Diego (USA) worked with a mouse model of human Alzheimer's disease. They treated some of the animals with two developmental drugs, E64d and CA074Me, which are known to inhibit the activity of the proteolytic enzyme cathepsin B. Results published in the March 21, 2008, issue of the Journal of Biological Chemistry revealed that the two compounds blocked BACE activity.

Treatment of London APP mice, expressing the wild type beta-secretase site, with these inhibitors resulted in substantial improvement in memory deficit assessed by the Morris water maze test. After inhibitor treatment, the improved memory function was accompanied by reduced amyloid plaque load. No such effects were found with a different strain of mice that expressed the Swedish mutant â-secretase site (found in fewer than 1% of Alzheimer's disease patients).

"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 Alzheimer's disease,” said senior author Dr. Vivian Y. H. Hook, professor of neurosciences at the University of California, San Diego.


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