Study On The Pathogenesis And Prevention Of Alzheimer's Disease (AD)

Accumulation of proteins after misfolding results in many diseases that greatly endanger human health,such as Alzheimer's disease.Recent experimental evidence indicates that these diseases are directly related to the accumulation of misfolded proteins on neurons or other cell surfaces.Although it has been studied for many years,the problems of the accumulation mechanism of misfolded proteins and the accumulation of cytotoxicity have not yet been clarified.This project intends to use molecular dynamics simulations to study the molecular dynamics of amyloid-??A??_16-21peptides?KLVFFA?,which is closely related to protein conformational disease,in the early stages of accumulation,during the rapid growth phase of the fibril,and the underlying molecular mechanism.The inhibitory effect of the accumulation of the small molecule drug lanosterol on the A?peptide and the disruption and mechanism of the mature peptide of the A?peptide chain,as well as the alleviating effect on the physiological toxicity of accumulation,were investigated through multi-level experimental methods and molecular dynamics simulations.Here,we combined computational and experimental approaches to study how lanosterol disrupts the aggregation of amyloid-??A??peptides,which eventually leads to the promotion of cell survival.Molecular dynamics simulation using the core amyloidogenic segment?KLVFFA?of A?peptide revealed lanosterol exhibits at least two types of the inhibition mechanism on the self-assembly of A?peptides.First,lanosterol entangles with peptides and forms a hydrophobic core with the residues Phe-19 and Phe-20.Second,it interferes the steric zipper interaction at the?-sheet-?-sheet interface.Our simulation results showed that lanosterol induces the unfolding of A?peptide and the separation of the?-sheet layers.The inhibition effect of lanosterol was also confirmed by in vitro ThT fluorescence assay and in the AFM image.Live/Dead viability assay showed that treatment of lanosterol mitigates the cytotoxicity of A?peptide in vivo in PC-12 cells.In this work,we used a combination of theoretical calculations and experiments to investigate how lanosterol disrupts the aggregation of the amyloid?A??peptide chain and ultimately promotes cell survival.This result establishes a foundation for the development of lanosterol-based potential therapies for AD and other protein conformational diseases.Amyloid-??A??peptide is thought to play an important role in the development of the Alzheimer's disease?AD?.