The accumulation of amyloid plaque deposits, composed primarily of the neurotoxic beta-amyloid (Aâ) peptide, is a hallmark sign of Alzheimer's disease.
One drug strategy to fight the disease is to reduce the production of Aâ 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 Aâ 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 Alzheimer's 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 Aâ 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 Alzheimer's cases — but not the Swedish mutant site.
The researchers also tested compounds that inhibit CatB - E64d and CA074Me -in a mouse model of Alzheimer's 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 Alzheimer's 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 Alzheimer's disease in the more than 99 per cent of individuals with the normal beta-secretase site.
"By disabling the enzyme's ability to cut the 'beta' end of the amino acid sequence, researchers may discover a way to limit production of neurotoxic Aâ 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.