Co-aggregation of α-synuclein with amyloid-β stabilizes β-sheet-rich oligomers and enhances the formation of β-barrels

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases with markedly different pathological features of β-amyloid (Aβ) plaques and α-synuclein (αS) Lewy bodies (LBs), respectively. However, clinical overlaps in symptoms and pathologies between AD and PD are commonly observed caused by the cross-interaction between Aβ and αS. To uncover the molecular mechanisms behind their overlapping symptoms and pathologies, we computationally investigated the impact of αS on an Aβ monomer and dimerization using atomistic discrete molecular dynamics simulations (DMD). Our results revealed that αS could directly interact with Aβ monomers and dimers, thus forming β-sheet-rich oligomers, including potentially toxic β-barrel intermediates. The binding hotspot involved the second half of the N-terminal domain and NAC region in αS, along with residues 10–21 and 31–42 in Aβ. In their hetero-complex, the binding hotspot primarily assumed a β-sheet core buried inside, which was dynamically shielded by the highly charged, amyloid-resistant C-terminus of αS. Because the amyloid prion region was the same as the binding hotspot being buried, their fibrillization may be delayed, causing the toxic oligomers to increase. This study sheds light on the intricate relationship between Aβ and αS and provides insights into the overlapping pathology of AD and PD.