Aggregation Mechanism of Alzheimer's Amyloid β-Peptide Mediated by α-Strand/α-Sheet Structure

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and a widespread form of dementia. Aggregated forms of the amyloid beta-peptide (A beta) are identified as a toxic species responsible for neuronal damage in AD. Extensive research has been conducted to reveal the aggregation mechanism of A beta. However, the structure of pathological aggregates and the mechanism of aggregation are not well understood. Recently, experimental studies have confirmed that the alpha-sheet structure in A beta drives aggregation and toxicity in AD. However, how the alpha-sheet structure is formed in A beta and how it contributes to A beta aggregation remains elusive. In the present study, molecular dynamics simulations suggest that A beta adopts the alpha-strand conformation by peptide-plane flipping. Multiple alpha-strands interact through hydrogen bonding to form alpha-sheets. This structure acts as a nucleus that initiates and promotes aggregation and fibrillation of A beta. Our findings are supported by previous experimental as well as theoretical studies. This study provides valuable structural insights for the design of anti-AD drugs exploiting the alpha-strand/alpha-sheet structure.