Researchers in Spain have reported an experimental peptide that reduced amyloid-beta production in cultured neurons and lowered amyloid plaque burden in a mouse model of Alzheimer’s disease. The work is early-stage, but it points to a possible way of targeting a protein involved in amyloid formation without fully shutting down its other functions.
The study was led by the Molecular and Cellular Neurobiotechnology group at the Institute for Bioengineering of Catalonia, working with collaborators at the Institute for Advanced Chemistry of Catalonia, the University of Barcelona and IRB Barcelona. It was published in Bioorganic Chemistry.
Targeting the molecular “scissors”
Amyloid beta, often abbreviated Aβ, is a protein fragment that can accumulate in the brains of people with Alzheimer’s disease. One enzyme involved in producing it is BACE1, which cuts a larger precursor protein and helps initiate the process that generates amyloid beta.
Previous efforts to block BACE1 completely have struggled in clinical trials. The enzyme has necessary biological roles, so broad inhibition can create side effects. The new approach instead seeks to selectively slow BACE1 activity.
The team designed short protein-like chains called peptides and chemically modified them to make them more durable in the body and capable of entering cells. One candidate, called P33, emerged from a library of 50 molecules tested in cultured neurons.
Results in cells and mice
According to the researchers, P33 reduced amyloid-beta release to less than half in cultured mouse neurons without damaging the cells. It also reduced BACE1-associated activity by more than 50% while not significantly affecting BACE2, a closely related enzyme.
The group then tested the peptide in genetically modified mice that develop amyloid plaques. After eight weeks of treatment, brain amyloid-beta levels and the plaque-covered area in the cortex and hippocampus were reduced by 35.6%, the report says. The source text also reports no observed damage to other organs or changes in inflammation markers during the study.
What the findings do—and do not—show
The findings are a preclinical result, not evidence of a treatment for people. The experiments were conducted in cell cultures and a mouse model, and the supplied report does not describe human trials. Alzheimer’s disease is biologically complex, and reductions in amyloid markers in animal studies do not by themselves establish clinical benefit.
Still, selective modulation of BACE1 could be important if it proves possible to preserve essential enzyme functions while reducing excess amyloid-beta production. The peptide’s apparent selectivity for BACE1 over BACE2 is therefore central to the result.
A potential starting point, not a finished drug
P33 will need substantially more testing before its therapeutic potential can be assessed. That includes confirming safety, determining how the molecule moves through the body, establishing an appropriate dose and evaluating whether it affects cognition or other disease measures in additional models.
For now, the study adds another strategy to Alzheimer’s research: rather than attempting to eliminate a target enzyme’s activity, researchers may be able to tune it. Whether that approach can translate from mice to patients remains an open question.
This article is based on reporting by Medical Xpress. Read the original article.
Originally published on medicalxpress.com
