For decades, researchers have invested billions of dollars in Alzheimer’s treatments designed to target beta-amyloid, a peptide that forms harmful deposits in the brain. But a biochemist at the University of California, Santa Cruz, believes scientists may have overlooked another potential contributor to the disease: a smaller, closely related peptide that has long been considered harmless.
In a new comment published in ChemBioChemJevgenij Raskatov, a professor at UC Santa Cruz, highlights research suggesting that this lesser-known peptide, called P3, can form microscopic clumps and threadlike structures called fibrils. Evidence also suggests that P3 may interact with beta-amyloid (Aβ), potentially influencing how it accumulates in the brain and its degree of toxicity. These results raise the possibility that P3 contributes to nerve cell damage associated with Alzheimer’s disease.
“The P3 peptide is probably not the innocent bystander that was commonly thought. There is still research to be done. But it could shake up Alzheimer’s disease research,” said Raskatov, whose lab studies amyloid peptides in hopes of identifying ways to prevent their harmful effects and develop better treatments for Alzheimer’s disease. “P3 is a distinct aggregating peptide that is itself potentially neurotoxic and may contribute to Alzheimer’s disease.”
Why treatments for Alzheimer’s disease have had limited success
Alzheimer’s disease is the most common neurodegenerative disease, affecting approximately 35 million people worldwide and generating annual costs exceeding $800 billion. The number of people living with the disease is expected to double by 2050.
Despite decades of intensive research, developing effective treatments has proven extremely difficult. More than 400 clinical trials have studied potential Alzheimer’s drugs, with most focusing on beta-amyloid. Many of these efforts failed, while others produced only modest benefits. Some treatments have also been linked to serious complications, including brain hemorrhages and strokes.
Beta-amyloid comes from a much larger protein embedded in cell membranes called amyloid precursor protein (APP). Two enzymes, β-secretase and γ-secretase, cut this protein in sequence, releasing beta-amyloid peptides of different lengths.
The researchers particularly focused on two versions, Aβ40 and Aβ42, which contain 40 and 42 amino acids, respectively. Aβ42 has attracted the most attention because it is particularly prone to sticking together and forming toxic aggregates. As a result, it has remained a central target of Alzheimer’s disease drug development for decades.
Existing medications, including cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, can temporarily relieve some symptoms but do not prevent disease progression. More recently, antibody treatments such as Lecanemab and Donanemab have been approved to help clear beta-amyloid from the brain.
However, Raskatov says the benefits achieved so far remain limited, highlighting the need to study other biological processes involved in Alzheimer’s disease.
“Progress has been extremely slow and the current state of knowledge in the treatment of Alzheimer’s disease leaves much to be desired,” he said. “We need fundamentally new approaches to the problem.”
The overlooked peptide that can also damage brain cells
Unlike beta-amyloid, P3 forms when the amyloid precursor protein is processed by a different sequence of molecular cuts. In this pathway, an enzyme called α-secretase acts first, followed by γ-secretase.
Raskatov proposed calling this peptide “Amyloid α” or Aα, to better distinguish it from amyloid beta and reflect its ability to form aggregates.
For years, scientists widely assumed that P3 was incapable of forming amyloid deposits, was not toxic to cells, and would remain soluble in water. According to this interpretation, the peptide would simply dissolve rather than accumulate in the brain.
These hypotheses have never been properly verified, according to Raskatov. Nonetheless, they helped establish the idea that P3 is unlikely to be important in Alzheimer’s disease, leaving it largely absent from research efforts.
Raskatov, a specialist in peptide chemistry, and researchers in his laboratory decided to test these long-held beliefs.
Over the past five years, the team has published three major studies demonstrating that P3 can form amyloid deposits at least as easily as beta-amyloid. In fact, their experiments showed that P3 produces these aggregates more quickly.
The researchers also found evidence that P3 itself may be harmful to neurons, although its toxicity appears lower than that of beta-amyloid.
According to Raskatov, an independent research group in the United Kingdom confirmed and expanded on his team’s findings. Other labs are now beginning to study how P3 and beta-amyloid interact, including whether their relationship affects the accumulation and toxicity of these peptides.
Together, the results challenge the long-held assumption that P3 is biologically harmless and unrelated to Alzheimer’s disease. However, more research is needed to determine if and how this contributes to disease in patients.
Difficult decades of Alzheimer’s research
For much of the past decades, beta-amyloid has dominated scientific explanations of Alzheimer’s disease. David Teplow, professor emeritus of neurology at UCLA and a leading Alzheimer’s disease researcher, said the peptide has long been considered a central cause of the disease.
But an independent assessment of Raskatov’s research led Teplow to conclude that scientists are beginning to reconsider this narrow view.
“This reevaluation has far-reaching implications for both basic science and clinical research into the causes and treatment of Alzheimer’s disease,” said Teplow, a founding member of the editorial board of the Journal of Molecular Neuroscience and the American Journal of Neurodegenerative Diseasesas well as editor-in-chief of Advances in molecular biology and translational science.
Raskatov also encountered a troubling problem in examining how other scientists interpreted his team’s findings.
He identified at least four papers published in respected peer-reviewed journals citing his lab’s research as evidence that P3 was harmless and incapable of forming amyloid deposits. However, his team’s experiments demonstrated exactly the opposite.
“This is the exact opposite of what we actually demonstrated,” Raskatov said. “We still don’t know how this sort of big confusion could have happened. Obviously, we still have work to do.”
Emerging evidence suggests that understanding Alzheimer’s disease may require looking beyond just beta-amyloid. By examining P3 and its interactions with other amyloid peptides, researchers hope to gain a more complete picture of the processes that damage brain cells and potentially identify new directions for treatment.
Gn Health
