Offering a potential early intervention for Alzheimer’s disease (AD), researchers at University of California, San Diego School of Medicine and Cenna Biosciences, Inc. have identified compounds that block the production of beta amyloid peptides in mice. The study is reported April 29 in PLOS ONE.
If the results ultimately translate to human treatment, the most promising compound – a peptide dubbed P8 – could be administered to individuals at high risk of developing the disease, long before the tell-tale signs of dementia occur and perhaps with few side effects, due to the compound’s highly specific mode 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 build-up of beta amyloid plaques is widely believed to cause irreversible brain damage, resulting in a host of cognitive and motor impairments broadly associated with AD, which accounts for about 60 to 80 percent of all cases of dementia in the United States.
Because of the currently perceived role of beta amyloid in disease progression, several investigational drugs have targeted the enzymes that cleave beta amyloid from its larger precursor protein, the aptly named amyloid precursor protein (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 does not act on enzymes, but rather binds to APP and in so doing, prevents the larger protein from being processed into smaller amyloid peptides. The compounds are derived from a fragment of a membrane protein known as presenilin 1 that is known to interact with APP to produce beta amyloid. The highly specific binding between the APP and P8 was measured using both biophysical methods and optical imaging techniques.
“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.
In addition to cell culture experiments, researchers also conducted experiments with mice, engineered to produce large amounts of the human beta amyloid early in life.
Their experiments showed that a two-week course of treatment with either P8 or another compound called P4 resulted in, on average, a greater than 50 percent reduction in plaque accumulation, as compared with mice who received 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,” she said. “It’s a real chance at a successful treatment for Alzheimer’s disease.”
Other co-authors include Eliezer Masliah, Edward Rockenstein, Martha Harber, and Taylor Horwood, UC San Diego; and Mihyun Kim, UC San Diego and Cenna Biosciences.
Funding: Funding for the study came, in part, from National Institutes of Health (grants 5RO1NS055161, 5RO1AG17888 and 1R43AG043278) and Alzheimer’s Drug Discovery Foundation.
Disclosure: Dewji and co-author S. Jonathan Singer, PhD, professor emeritus in the Division of Biological Sciences, founded Cenna in 2006. The technology that forms the basis of Cenna’s approach and lead compounds is covered by U.S. and foreign patent applications filed by UC San Diego and exclusively licensed to Cenna.
Source: Scott LaFee – UCSD
Image Credit: The image is credited to Dewji et al./PLOS ONE
Original Research: Full open access research for “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” by Nazneen N. Dewji, S. Jonathan Singer, Eliezer Masliah, Edward Rockenstein, Mihyun Kim, Martha Harber, and Taylor Horwood in PLOS ONE. Published online April 29 2015 doi:10.1371/journal.pone.0122451
Abstract
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
β-Amyloid (Aβ) accumulation in the brain is widely accepted to be critical to the development of Alzheimer’s disease (AD). Current efforts at reducing toxic Aβ40 or 42 have largely focused on modulating γ-secretase activity to produce shorter, less toxic Aβ, while attempting to spare other secretase functions. In this paper we provide data that offer the potential for a new approach for the treatment of AD. The method is based on our previous findings that the production of Aβ from the interaction between the β-amyloid precursor protein (APP) and Presenilin (PS), as part of the γ-secretase complex, in cell culture is largely inhibited if the entire water-soluble NH2-terminal domain of PS is first added to the culture. Here we demonstrate that two small, non-overlapping water-soluble peptides from the PS-1 NH2-terminal domain can substantially and specifically inhibit the production of total Aβ as well as Aβ40 and 42 in vitro and in vivo in the brains of APP transgenic mice. These results suggest that the inhibitory activity of the entire amino terminal domain of PS-1 on Aβ production is largely focused in a few smaller sequences within that domain. Using biolayer interferometry and confocal microscopy we provide evidence that peptides effective in reducing Aβ give a strong, specific and biologically relevant binding with the purified ectodomain of APP 695. Finally, we demonstrate that the reduction of Aβ by the peptides does not affect the catalytic activities of β- or γ-secretase, or the level of APP. P4 and P8 are the first reported protein site-specific small peptides to reduce Aβ production in model systems of AD. These peptides and their derivatives offer new potential drug candidates for the treatment of AD.
“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” by Nazneen N. Dewji, S. Jonathan Singer, Eliezer Masliah, Edward Rockenstein, Mihyun Kim, Martha Harber, and Taylor Horwood in PLOS ONE. Published online April 29 2015 doi:10.1371/journal.pone.0122451
