A biochemist at the University of California, Santa Cruz, is challenging decades of Alzheimer’s disease research, suggesting a previously overlooked peptide, P3, may be a key contributor to the disease’s progression. The findings could explain why current Alzheimer’s treatments, largely focused on amyloid beta (Aβ), have shown limited success.
Jevgenij Raskatov, a professor at UC Santa Cruz, argues that P3, sometimes referred to as “Amyloid α,” forms toxic clumps as readily as, and potentially even faster than, Aβ. His research, published in the journal ChemBioChem, indicates P3 may similarly interact with Aβ, influencing its accumulation and toxicity. “The P3 peptide is, most likely, not the innocent bystander it was commonly thought to be,” Raskatov said. “There’s still more research to be done. But this could turn Alzheimer’s research on its head.”
Alzheimer’s disease affects approximately 35 million people worldwide and carries an annual cost exceeding $800 billion, with projections estimating a doubling of cases by 2050. Despite over 400 clinical trials, the majority targeting Aβ, have largely failed or yielded only modest results, often accompanied by serious side effects like cerebral hemorrhages and strokes. Current treatments, including cholinesterase inhibitors and NMDA receptor antagonists, primarily address symptoms rather than halting disease progression. More recently approved antibody therapies, such as Lecanemab, aim to clear Aβ from the brain, but have demonstrated limited efficacy to date.
The prevailing theory in Alzheimer’s research centers on Aβ, a peptide created when the Amyloid Precursor Protein (APP) is cleaved by β-secretase and γ-secretase. Aβ peptides of 40 and 42 amino acids—Aβ40 and Aβ42—have been the primary therapeutic targets, with Aβ42 considered particularly toxic due to its propensity to aggregate. However, Raskatov’s operate focuses on the alternative processing pathway of APP, where α-secretase and γ-secretase produce the P3 peptide. Previous research incorrectly assumed P3 was non-toxic and water-soluble, dismissing its potential role in the disease.
Raskatov’s lab demonstrated over the past five years that P3 is capable of forming amyloid deposits at a rate comparable to Aβ, and is potentially toxic to neurons, albeit to a lesser extent than Aβ. These findings have been independently validated by a research team in the UK, and other labs are beginning to investigate the interplay between Aβ and P3.
David Teplow, an emeritus professor of neurology at UCLA and a leading Alzheimer’s researcher, acknowledged the significance of Raskatov’s work. “This reevaluation has far-reaching consequences for both basic science and clinical research into the causes and treatment of Alzheimer’s disease,” Teplow said in an independent assessment.
Raskatov discovered discrepancies in published research, finding at least four peer-reviewed articles citing his lab’s work as evidence that P3 is harmless and does not form amyloid deposits—a direct contradiction of his findings. “This is exactly the opposite of what we have actually shown,” he 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.”
