For decades, the search for an Alzheimer’s treatment has centered on one major culprit—amyloid beta. But now, a University of California Santa Cruz chemist argues that scientists may have overlooked a closely related peptide long dismissed as harmless in their research.
In a commentary published in the peer-reviewed journal ChemBioChem, Jevgenij Raskatov, PhD, professor of chemistry and biochemistry at UC Santa Cruz, highlights new research which suggests that the lesser-known peptide, P3, can form the same clumps and fibrils as amyloid beta, the target of most Alzheimer’s drug development. P3 may also interact with amyloid beta, influencing how it builds up and how toxic it becomes.
These findings ultimately suggest that P3 may be contributing 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,” Raskatov said in a release. Instead, he’s proposed to rename it amyloid alpha, or Aα.
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What P3 is and why scientists dismissed it
Amyloid beta comes from a large protein embedded in cell membranes called the Amyloid Precursor Protein (APP). Two enzymes, β-secretase and γ-secretase, cut the protein in a sequence, freeing amyloid beta fragments of different lengths.
Previously, researchers have focused on two of those fragments, Aβ40 and Aβ42. Aβ42 has been reviewed the most because it is especially prone to sticking together and clumping into toxic aggregates.
But unlike amyloid beta, P3 forms when APP is processed through a different sequence of molecular cuts. The enzyme α-secretase acts first, and then γ-secretase, and P3 forms when alpha-secretase does. Researchers previously assumed that P3 stayed dissolved and didn’t clump, nor was it presumed to be toxic. But Raskatov did not believe that these assumptions were ever adequately tested.