摘要
Alzheimer's disease(AD)is closely linked to the accumulation of amyloid-beta peptides(Aβ),which impair synaptic plasticity and contribute to cognitive decline.Among the fragments of Aβ,the CT16 peptide(the equivalent of Aβ16,derived from soluble amyloid precursor proteinα,s APPα)has been shown to interact with theα7 nicotinic acetylcholine receptor(α7nAChR),potentially enhancing synaptic plasticity.However,the concentrationdependent modulation of CT16 onα7nAChR and its underlying mechanisms remain poorly understood.We employ molecular dynamics simulations to investigate how varying concentrations of CT16 affect the conformation and function of theα7nAChR,and establishes the proportional relationship between CT16 concentration andα7nAChR receptor function regulation at the molecular level,finding a stoichiometric ratio of 1:3 for maximum activation ofα7nAChR by CT16,and establishing the first demonstration that the constriction geometry of the pore within extracellular domain(specifically its minimal cross-sectional area)serves as the dominant structural determinant for ion permeation pathways at stoichiometric CT16:α7nAChR binding(1:1 ratio),a phenomenon contrasting sharply with scenarios at higher ratios(CT16:α7nAChR>1:1).The presence of CT16 not only induces significant conformational changes,stabilizes specific receptor regions,but also modulates the ion channel's pore geometry in a concentration-dependent manner.These findings shed light on the potential role of CT16 in regulating synaptic plasticity and offer theoretical insights into its dual role as a positive allosteric modulator at low concentrations and an inhibitor at higher concentrations,which may have implications for therapeutic strategies targetingα7nAChR in AD and other neurodegenerative diseases.
基金
supported by the Shandong Provincial Natural Science Foundation(ZR2022MB073)of China。
