They have found compounds that block the production of beta amyloid peptides in mice, which could provide an early intervention for Alzheimer's disease (AD).
The compound showing the greatest promise thus far-a peptide called P8-could be given to people found to be at high risk for the disease before symptoms are manifest, if the results bear out for human treatment.
"Our approach is completely different from any current approaches that target beta amyloid," says lead author Nazneen Dewji, PhD, associate adjunct professor, University of California, San Diego School of Medicine. "We are blocking the actual production of beta amyloid in a new way. It's very promising because it means that, in principle, we can stop the disease in its tracks."
The UCSD researchers worked alongside colleagues from biopharma company Cenna Biosciences, Inc, La Jolla, Calif, which Dewji and co-author S. Jonathan Singer, PhD, professor emeritus, Division of Biological Sciences, founded in 2006. Dewji serves as the company's president and CEO.
Accumulation of amyloid plaque is generally thought to cause permanent brain damage. Patients may have a range cognitive and motor damage chiefly connected with AD, which accounts for some 60 to 80 percent of all cases of dementia in the United States.
Due to beta amyloid's implication in the progression of the disease, a number of investigational drugs zero in on enzymes that cleave beta amyloid from its larger precursor protein-amyloid precursor protein (APP).
"These drugs, however, have largely failed in clinical trials, mostly because they are responsible for cleaving other proteins besides APP," Dewji says. "Inhibiting or modifying their activities creates many undesirable effects in the cell."
The P8 compound binds to APP and in the process, thwarts the larger protein from being processed into smaller amyloid peptides.
"Our approach is different, specific, and interferes with only the reaction that produces beta amyloid, as opposed to drugs that target the enzymes responsible for its cleavage from APP, which can affect multiple reactions in cells," Dewji says. Cenna is developing potential drug candidates.
The researchers also performed experiments with young mice designed to generate large amounts of the human beta amyloid. They found that a two-week course of treatment with P8 or a different compound called P4 culminated in, on average, a decline of more than 50 percent in plaque accumulation, versus mice who had no treatment.
"We now have a new approach for the treatment of Alzheimer's disease that can arrest the production of beta amyloid very early and specifically," Dewji says. "It's a real chance at a successful treatment for Alzheimer's disease."
The study, in an article titled "Peptides of Presenilin-1 Bind the Amyloid Precursor Protein Ectodomain and Offer a Novel and Specific Therapeutic Approach to Reduce ß-Amyloid in Alzheimer's Disease," is reported in PLOS ONE.
[Source: UCSD]