A research team led by the Molecular and Cellular Neurobiotechnology group at the Institute for Bioengineering of Catalonia (IBEC) , in collaboration with Míriam Royo’s laboratory at the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) , the University of Barcelona (UB) and the Institute for Research in Biomedicine (IRB Barcelona) , has identified a synthetic peptide that reduces the production of amyloid beta (Aβ). This protein builds up in the brain in Alzheimer’s disease. The work, published in the journal Bioorganic Chemistry , was carried out in cultured neurons ( in vitro ) and in a mouse model of the disease ( in vivo ).
An enzyme, BACE1, is involved in the production of Aβ. Enzymes are proteins that facilitate chemical reactions in cells; in this case, BACE1 acts like a pair of “scissors” that cuts another protein, giving rise to amyloid beta. Drugs designed to block it completely have not succeeded in clinical trials, partly because of the side effects of also blocking other necessary functions of the enzyme. The team tried a different strategy: they designed peptides, short chains like those that make up proteins, and modified them chemically so that the body does not break them down quickly and so that they can enter cells, where amyloid beta is produced.
“ We analysed a library of 50 of these molecules in cultured neurons. P33 stood out because it clearly reduced amyloid beta without damaging the cells and, in addition, selectively slowed down BACE1 activity ,” explains Dayaneth Jácome , first author of the study and researcher at IBEC.
In cultured mouse neurons, P33 reduced Aβ release to less than half without damaging the cells. It also decreased BACE1-associated activity by more than 50%, without significantly affecting a very similar enzyme, BACE2. In mice genetically modified to develop amyloid plaques, administering P33 for eight weeks reduced by 35.6% the levels of brain Aβ and the area covered by plaques in the cortex and hippocampus. No damage to other organs or changes in the inflammation markers analysed were detected.
“ Our results show that it is not necessary to block BACE1 completely to reduce amyloid beta production, at least in laboratory models. These peptides give us a versatile chemical platform to keep investigating this pathway ,” explains José A. Del Río , principal investigator at IBEC, Full Professor at the Faculty of Biology of the University of Barcelona (UB), member of the UB Institute of Neurosciences (UBneuro) and CIBERNED, and co-leader of the study.
“ These first results in mice open up several lines of work. We now want to expand the studies with a larger number of animals, measure how much P33 reaches the brain and confirm precisely how it acts on BACE1 ,” says Rosalina Gavín , co-leader of the study, senior researcher at IBEC, Associate Professor at the UB and member of UBneuro and CIBERNED. The team also wants to check whether the trend towards better memory shown by the treated mice is confirmed in larger studies.
Bioorganic Chemistry
Experimental study
Animals
cis-γ-Amino-L-proline peptides as chemical probes of amyloidogenic processing in neurons and APP/PS1 mice
15-Aug-2026
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.