Formation of a β‐Endorphin Corona Mitigates Alzheimer's Amyloidogenesis

Senile plaques, comprised of nanosized aggregates of amyloid-β (Aβ) peptides in the brain, are a pathological hallmark of Alzheimer's disease (AD). On the other hand, regular physical exercise is known to significantly reduce the risk of developing AD. Here, it is reported on the transformation and toxicity mitigation of Aβ amyloid aggregation by a spontaneous "corona" of β-endorphin, a major peptide hormone released upon exercise to suppress post-exercise pain. Given that both Aβ and β-endorphin co-localize extracellularly in the brain, it is postulated that β-endorphin may mitigate the toxicity of Aβ aggregation via direct molecular interactions, thereby contributing to an exercise-mediated reduction of AD risk. Combining biophysical characterizations in vitro with atomistic discrete molecular dynamics simulations in silico, a strong interaction is shown between β-endorphin and Aβ, where β-endorphins are located at the periphery to render a corona of their hetero-complexes with Aβ. Cell viability, immunofluorescence and western blotting assays further revealed that the corona shielded cellular exposure to Aβ aggregates and suppressed the toxicity of Aβ in vivo. This work offered a new molecular mechanism for the benefits of physical exercise, which may facilitate a rational design of future therapy and prevention strategies against AD and dementia.