Molecular mechanism of Alzheimer's p-amyloid peptide aggre-gation
Alzheimer's disease(AD)is a typical neurodegenerative disease.The common symptoms of AD include memory loss,decline in language abilities,impaired orientation,and cognitive skills deterioration.One of the major pathological hallmarks involved in AD is amyloid plaque deposition,which are amyloid deposits formed by aberrant aggregation of β-amyloid peptide(Aβ).Aβ is the cleavage product by β-and y-secretases acting on amyloid precursor protein under the amyloidogenic pathway.It is prone to aggregate from their disordered monomeric state into a highly ordered aggregated state.The underlying microscopic mechanism of Aβ aggregation comprises nucleation and elongation steps.The resulting pathological amyloid fibrils formation and the spread of these amyloid fibrils in cells are linked to AD pathogenesis.The Aβ aggregation is the causative agent of Alzheimer's pathology and results in axonal disruption,synapse loss,and ultimately cell death.Liquid-liquid phase separation(LLPS)driven protein aggregation has been observed to form pathological inclusions associated with neurodegenerative diseases,including amyotrophic lateral sclerosis,Parkinson's disease,and AD.In addition to misfolding and aggregation,several of these disease-associated proteins undergo LLPS forming dynamic condensates,further modulating the aggregation process.Recent research reported that one of the pathogenic Aβ oligomer species can undergo phase separation in vitro and this LLPS modulates a liquid-to-solid phase transition and redirects the aggregation pathway to form pathogenic amyloid fibrils.The regulatory role of LLPS underlies Aβ peptide aggregation and may inform future AD therapeutics.Amyloid fibrils,as the final amyloid protein aggregation product,have been extensively studied due to the significant role of the molecular structure on the pathological characteristics of AD.However,owing to the complex nucleation and aggregation process,amyloid polymorphism and structural heterogeneity have been reported during Aβ aggregation.Benefit from the technological development of magic angle spinning(MAS)solid-state nuclear magnetic resonance(ssNMR)and single-particle cryogenic electron microscopy(cryo-EM),the molecular structures of Aβ fibrils have been determined both in vitro and in vivo over the last few decades.In general,amyloid fibril adopt β-conformation and assemble into a common cross-β fibril spine structure.Although significant progress has been achieved during the last hundred years,there are still enormous challenges in AD pathology,early diagnosis,and effective treatment.The aggregation mechanism and Aβ species toxicity,the link between structure and toxicity,the relationship between amyloid polymorphism and disease progression are still not fully understood.This paper focuses on the aggregation process of the Aβ peptide,including primary nucleation,elongation,and secondary nucleation steps.We describe LLPS phenomenon in the early phase of Aβ aggregation and the vital roles of phase separation and phase transition in the aggregation process.We summarize amyloid polymorphism and the current molecular structures of Aβ fibrils formed during aggregation.This review will provide better understanding of the relationship between the aggregation mechanism and the cytotoxicity of diverse Aβ species to shed light on the disease progression and hope to offer a solution for treatment of AD by regulating the aberrant aggregation and phase transition.
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