Scientists have long searched for ways to treat Alzheimer’s disease, the most common form of dementia.
Chief among these strategies has been targeting amyloid beta, a toxic protein that forms plaque-like deposits when it accumulates abnormally in the brain. This accumulation is a hallmark of Alzheimer’s.
Now, scientists say a smaller peptide, a “cousin” of amyloid beta, could also be neurotoxic.
Recent research in the journal ChemBioChem suggests that this peptide, known as P3, can also form dangerous brain clumps and could interact with amyloid beta in ways that support accumulation and toxicity, thereby contributing to neurodegeneration.
“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 UC Santa Cruz professor Jevgenij Raskatov.
“P3 is a distinct aggregating peptide that is itself potentially neurotoxic and may be contributing to Alzheimer’s disease.”
Alzheimer’s is marked by a decline in memory, thinking and learning. Nearly 7 million Americans are living with the condition, but researchers say millions more likely have symptoms but no formal diagnosis.
Previous research has theorized that P3 was non-toxic, water-soluble and would dissolve in the brain, preventing plaque accumulation.
Due to this assumption, P3 has been largely dismissed as a potential contributor to Alzheimer’s.
However, through their research, Raskatov and his team have demonstrated that P3 is as capable as amyloid beta of forming amyloid deposits — and does so more rapidly.
In addition, they found that while less toxic than amyloid beta, P3 still poses a serious threat to neurons.
Disconcertingly, Raskatov’s research has been wildly misinterpreted: four scientific articles in reputable journals have cited his work as evidence that P3 is a benign peptide that does not form amyloid.
“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.”
In terms of treatment, Raskatov notes that the majority of the 400-plus clinical trials for Alzheimer’s drugs have targeted amyloid beta — and have largely failed or shown modest results with serious side effects.
Cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists can offer patients relief but do not impede disease progression.
More recently, medications like lecanemab and donanemab have been shown to improve mild cognitive impairment or dementia by clearing amyloid plaques from the brain.
Raskatov maintains that the development of Alzheimer’s treatments has been less than stellar, and the new information about P3 could help it get back on track.
“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.”
