Amyloid‑α
Peptide Formed through Alternative
Processing of the Amyloid Precursor Protein Attenuates Alzheimer’s
Amyloid‑β Toxicity via Cross-Chaperoning
posted on 2024-01-18, 14:19authored byAriel J. Kuhn, Ka Chan, Maria Sajimon, Stan Yoo, Vitor Hugo Balasco Serrão, Jack Lee, Benjamin Abrams, James S. Nowick, Vladimir N. Uversky, Christopher Wheeler, Jevgenij A. Raskatov
Amyloid
aggregation is a key feature of Alzheimer’s disease
(AD) and a primary target for past and present therapeutic efforts.
Recent research is making it increasingly clear that the heterogeneity
of amyloid deposits, extending past the commonly targeted amyloid-β
(Aβ), must be considered for successful therapy. We recently
demonstrated that amyloid-α (Aα or p3), a C-terminal peptidic
fragment of Aβ, aggregates rapidly to form amyloids and can
expedite the aggregation of Aβ through seeding. Here, we advance
the understanding of Aα biophysics and biology in several important
ways. We report the first cryogenic electron microscopy (cryo-EM)
structure of an Aα amyloid fibril, proving unambiguously that
the peptide is fibrillogenic. We demonstrate that Aα induces
Aβ to form amyloid aggregates that are less toxic than pure
Aβ aggregates and use nuclear magnetic resonance spectroscopy
(NMR) to provide insights into specific interactions between Aα
and Aβ in solution. This is the first evidence that Aα
can coassemble with Aβ and alter its biological effects at relatively
low concentrations. Based on the above, we urge researchers in the
field to re-examine the significance of Aα in AD.