For decades, researchers have invested billions of dollars in Alzheimer’s treatments designed to target amyloid beta, 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 was long considered harmless.
In a new commentary published in ChemBioChem, UC Santa Cruz professor Jevgenij Raskatov highlights research suggesting that this lesser-known peptide, called P3, can form microscopic clumps and threadlike structures known as fibrils. Evidence also suggests that P3 may interact with amyloid beta (Aβ), potentially influencing how it accumulates in the brain and how toxic it becomes. These findings raise the possibility that P3 contributes to the nerve cell damage associated with Alzheimer’s disease.
“The P3 peptide is, most likely, not the innocent bystander it was commonly thought to be. There’s still more research to be done. But this could turn Alzheimer’s research on its head,” said Raskatov, whose laboratory investigates amyloid peptides in hopes of identifying ways to prevent their harmful effects and develop better Alzheimer’s treatments. “P3 is a distinct aggregating peptide that is itself potentially neurotoxic and may be contributing to Alzheimer’s disease.”
Why Alzheimer’s Treatments Have Had Limited Success
Alzheimer’s is the most widespread neurodegenerative disease, affecting approximately 35 million people worldwide and generating annual costs exceeding $800 billion. The number of people living with the condition is expected to double by 2050.
Despite decades of intensive research, developing effective treatments has proved extraordinarily difficult. More than 400 clinical trials have investigated potential Alzheimer’s drugs, with most focusing on amyloid beta. Many of these efforts have failed, while others have produced only modest benefits. Some treatments have also been associated with serious complications, including brain hemorrhages and strokes.
Amyloid beta originates from a much larger protein embedded in cell membranes called the Amyloid Precursor Protein (APP). Two enzymes, β-secretase and γ-secretase, cut this protein in sequence, releasing amyloid beta peptides of different lengths.
Researchers have concentrated particularly on two versions, Aβ40 and Aβ42, which contain 40 and 42 amino acids, respectively. Aβ42 has attracted the greatest attention because it is especially prone to sticking together and forming toxic aggregates. As a result, it has remained a central target of Alzheimer’s drug development for decades.
Existing medications, including cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, can temporarily ease certain symptoms but do not stop the disease from progressing. More recently, antibody treatments such as Lecanemab and Donanemab have been approved to help remove amyloid beta from the brain.
However, Raskatov argues that the benefits achieved so far remain limited, underscoring the need to investigate other biological processes involved in Alzheimer’s.
“Progress has been extremely slow, and the current state of the art in Alzheimer’s therapy leaves much to be desired,” he said. “We need fundamentally new approaches to the problem.”
The Overlooked Peptide That May Also Damage Brain Cells
Unlike amyloid beta, P3 forms when Amyloid Precursor Protein is processed through a different sequence of molecular cuts. In this pathway, an enzyme called α-secretase acts first, followed by γ-secretase.
Raskatov has 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 largely assumed that P3 was incapable of forming amyloid deposits, was not toxic to cells, and would remain soluble in water. Under that interpretation, the peptide would simply dissolve rather than accumulate in the brain.
These assumptions were never adequately verified, according to Raskatov. Nevertheless, they helped establish the view that P3 was unlikely to matter 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 those long-standing beliefs.
Over the past five years, the team has published three major studies demonstrating that P3 can form amyloid deposits at least as readily as amyloid beta. In fact, their experiments showed that P3 produces these aggregates more rapidly.
The researchers also found evidence that P3 itself may be harmful to neurons, although its toxicity appears lower than that of amyloid beta.
According to Raskatov, an independent research group in the United Kingdom has confirmed and expanded upon his team’s findings. Other laboratories are now beginning to investigate how P3 and amyloid beta 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 irrelevant to Alzheimer’s. However, further research is needed to establish whether and how it contributes to the disease in patients.
Challenging Decades of Alzheimer’s Research
For much of the past several decades, amyloid beta has dominated scientific explanations of Alzheimer’s disease. David Teplow, an emeritus professor of neurology at UCLA and a prominent Alzheimer’s researcher, said the peptide has long been regarded as a central cause of the condition.
But an independent evaluation of Raskatov’s research led Teplow to conclude that scientists are beginning to reconsider this narrow focus.
“This reevaluation has far-reaching consequences for both basic science and clinical research into the causes and treatment of Alzheimer’s disease,” said Teplow, a founding editorial board member of the Journal of Molecular Neuroscience and the American Journal of Neurodegenerative Disease, as well as editor-in-chief of Progress in Molecular Biology and Translational Science.
Raskatov has also encountered a troubling problem while examining how other scientists have interpreted his team’s discoveries.
He identified at least four papers published in respected, peer-reviewed journals that cited his laboratory’s research as evidence that P3 was harmless and unable to form amyloid deposits. Yet his team’s experiments had demonstrated precisely the opposite.
“This is exactly the opposite of what we have actually shown,” Raskatov said. “We remain in the dark on how this sort of grand confusion may have come about. Clearly, there is more work ahead of us.”
The emerging evidence suggests that understanding Alzheimer’s may require looking beyond amyloid beta alone. 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.