Researchers Inhibit Production of Beta Amyloid Peptides in Alzheimer’s Disease Mouse Models

A team of researchers from the University of California, San Diego School of Medicine and Cenna Biosciences, Inc. were able to identify in mice, compounds that inhibit the production of beta amyloid peptides. The results published in the journal PLOS ONE may offer a potential early intervention for patients with Alzheimer’s disease (AD)

If these results are also achieved in humans, a peptide dubbed P8 could offer new potential drug candidates for the treatment of patients at risk of AD with few adverse effects, due to the compound’s highly specific mechanism of action.

“Our approach is completely different from any current approaches that target beta amyloid,” said lead author Nazneen Dewji, PhD, associate adjunct professor in the Department 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 molecular pathology of the disease includes the production and accumulation of beta amyloid plaques (Aβ) in the brain causing irreversible memory as well as cognitive and motor impairments. Aβ is the major neurotoxic agent in the initiation of AD, and it is a set of 39–43 amino acid oligopeptides, each of which is proteolytically cleaved from its precursor protein, APP. Several investigational drugs have targeted the enzymes that cleave beta amyloid from APP. “These drugs, however, have largely failed in clinical trials,” said Dewji, “mostly because they are responsible for cleaving other proteins besides APP. Inhibiting or modifying their activities creates many undesirable effects in the cell.”

The P8 compound binds to APP and averts the processing of the larger protein into smaller amyloid peptides. P8 is derived from presenilin 1, a fragment of a membrane protein that interacts with APP to produce beta amyloid. In the study, the researchers measured the binding between the APP and P8 using biophysical techniques and optical imaging.

“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,” said Dewji, who is also president and CEO of the La Jolla-based biopharmaceutical company Cenna where the drug candidates are being developed.

The team also used in their experiments mice that were modeled to generate large amounts of the human beta amyloid early in life. Findings from their tests revealed that a treatment of two weeks with P8 or another agent named P4 caused an inhibition in the production of total Aβ plaque.

“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,” she said. “It’s a real chance at a successful treatment for Alzheimer’s disease.”