Scientists have reported on the possible role of the P3 peptide in Alzheimer's disease
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- Scientists have reported on the possible role of the P3 peptide in Alzheimer's disease
The P3 peptide, which has long been considered a relatively harmless protein processing product, may be involved in the processes associated with Alzheimer's disease. Laboratory studies have shown that it is able to form amyloid aggregates and interact with beta-amyloid, one of the main targets of existing treatment methods. Why the researchers propose to reconsider the role of P3, what results have already been obtained and what is preventing the transition from the molecular hypothesis to treatment — in the Izvestia material.
Why was attention focused on beta-amyloid
Beta-amyloid is a small fragment of a larger precursor protein APP located in the cell membrane. It is formed as a result of the sequential action of enzymes that break down the original molecule.
Aggregation means that individual molecules combine with each other. In this case, small associations may occur — oligomers, and then larger filamentous structures — fibrils. Amyloid deposits in the brain have become one of the most well-known signs of the disease.
However, Alzheimer's disease is not limited to the accumulation of a single peptide. According to the US National Institute of Aging, complex interactions of beta-amyloid, altered tau protein and other factors are involved in its development. Among the processes studied are inflammation, disruption of the functioning of supporting cells, and vascular changes.
Therefore, the question of P3 arises within the already complex picture of the disease. It concerns how fully the research takes into account the different processed products of the APP and their combined effect.
Where does P3 come from
An APP can be split in different ways. When beta-amyloid is formed, beta-secretase acts first, and then gamma-secretase. With an alternative sequence, alpha-secretase becomes the first enzyme, followed by gamma-secretase.
In the second case, a shorter P3 peptide is formed. Its amino acid sequence corresponds to a part of the beta-amyloid sequence: these are closely related molecules, but with different properties.
In the literature, an alternative way of processing APP has traditionally been described as non-amyloidogenic. According to the author of the comment, Evgeny Raskatov, a professor at the University of California at Santa Cruz, P3 was often considered unable to form amyloid, non-toxic and highly soluble.
The researcher believes that these ideas contributed to the lack of attention to the peptide. His laboratory decided to check whether the short fragment really behaves as expected.
Raskatov proposed the name "amyloid-alpha", or Aa, to designate P3. This is an author's proposal designed to emphasize the ability of the peptide to aggregate and distinguish it from beta-amyloid. It does not mean that a completely new molecule has been discovered in the brain: the properties of the long-known processing product APP are being reviewed.
What was seen in the laboratory
Back in 2020, Raskatov's group showed that P3 is capable of forming oligomers and fibrils. Under the studied conditions, aggregation occurred faster than that of beta-amyloid. Therefore, the authors suggested revising the usual definition of P3 as non-amyloidogenic.
The independent results were presented by researchers at Queen Mary University of London in a paper published in Nature Communications in 2025. They also discovered the rapid formation of fibrils and investigated the interaction of P3 with cell membranes.
In particular, experiments have shown that oligomers of one of the P3 variants can form ion channels in membranes. The authors studied the movement of calcium ions and cell viability, obtaining data on the potentially damaging effect of the peptide.
This expands the question beyond the mere presence of sediments. What may matter is how individual forms of the peptide interact with the cell, not just how quickly large aggregates appear.
"The P3 peptide is most likely not the harmless observer it was usually thought to be. There is still a lot of research to be done," Raskatov said.
At the same time, faster aggregation is not equivalent to proof of a greater danger to humans. The rate of formation of structures, their composition, and the effect on cells are related but different characteristics.
What is still unknown about the role of P3 in patients
The laboratory results provide grounds to investigate P3 further, but do not establish its contribution to the course of Alzheimer's disease in humans. The ability to form fibrils under controlled conditions, damage cells in an experiment, and participate in disease — varying levels of evidence. It is necessary to trace the connection between them.
To do this, it is important to determine which forms of P3 are present in the brain of patients, where they accumulate, and whether their number is related to neuron damage and the severity of symptoms. Then it will be necessary to check whether the pathological process changes when exposed to this peptide.
There is also a methodological difficulty. Since P3 is a fragment of the beta-amyloid sequence, it is not easy to distinguish between the two molecules and measure their content separately. In the commentary, Raskatov highlights the development of such methods as a separate task.
How the old view continues to influence research
A separate part of the discussion concerns how scientific conclusions are conveyed from article to article. Raskatov reported that he had found at least four peer-reviewed publications in which his laboratory's work was cited as evidence of the harmlessness of P3 and its lack of ability to form amyloid.
"This is the exact opposite of what we actually showed," Raskatov said.
This episode is important for evaluating evidence: the presence of a reference to a study does not guarantee that its result is presented correctly. Especially when it comes to revising the usual definition of a molecule.
But the criticism of citation alone also does not prove the causal role of P3 in the disease. It shows the need to more accurately describe already established properties and separate them from unresolved issues.
What difference can this make in finding treatment?
If the involvement of P3 in brain damage is confirmed, this may influence the choice of targets for future drugs. Researchers will have to take into account not only the amount of beta-amyloid, but also the formation of other APP fragments, as well as the properties of mixed aggregates.
This is especially important for approaches that try to change the way the APP is redesigned. The very decrease in the formation of one peptide does not yet describe the whole result, if the amount of another changes at the same time, the biological role of which has not been sufficiently studied.
However, it does not follow from the current data that P3 absolutely needs to be suppressed or deleted. Experiments with the joint assembly of peptides show that the outcome may depend on the specific forms and conditions of interaction.
The practical next step is to learn how to reliably distinguish between P3 and beta—amyloid in biological samples, determine their ratio, and verify the link with nerve tissue damage. Only then will it be possible to reasonably assess whether the effect on P3 has an additional therapeutic effect.
Work on P3 has so far expanded the understanding of the molecular processes associated with Alzheimer's disease. Their significance lies in verifying the long-held assumption about the safety of the peptide and in posing a more precise question.: how different products of the same precursor protein jointly affect the state of the brain.
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