Abstract
Increasing evidence shows that Aβ oligomers are key pathogenic molecules in Alzheimer’s disease. Among Aβ oligomers, dimer is the smallest aggregate and toxic unit. Therefore, understanding its structural and dynamic properties is quite useful to prevent the formation and toxicity of the Aβ oligomers. In this study, we performed molecular dynamic simulations on four Aβ42 dimers, 2NCb, CNNC, NCNC and NCCN, within the hydrated DPPC membrane. Four Aβ42 dimers differ in the arrangements of two Aβ42 peptides. This study aims to investigate the impact of aggregation pattern of two Aβ peptides on the structural stability of the Aβ42 dimer and its disruption to the biological membrane. The MD results demonstrate that the NCCN, CNNC and NCNC have the larger structural fluctuation at the N-terminus of Aβ42 peptide, where the β-strand structure converts into the coil structure. The loss of the N-terminal β-strand further impairs the aggregate ability of Aβ42 dimer. In addition, inserting Aβ42 dimer into the membrane can considerably decrease the average APL of DPPC membrane. Moreover this decrease effect is largely dependent on the distance to the location of Aβ42 dimer and its secondary structure forms. Based on the results, the 2NCb is considered as a stable dimeric unit for aggregating the larger Aβ42 oligomer, and has a potent ability to disrupt the membrane.
Highlights
Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder that is characterized by the impairment of memory, attention and executive function [1,2]
This study aims to investigate the impact of aggregation pattern of two Aβ peptides on the structural stability of the Aβ42 dimer and its disruption to the biological membrane
The cognitive impairment is mainly caused by the formation of senile plaques, which has been considered as a hallmark in the development of AD [3,4].The plaque deposits are primarily composed of insoluble fibrils that are aggregated from various amyloid-β (Aβ) peptides with 39–42 amino acids
Summary
Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder that is characterized by the impairment of memory, attention and executive function [1,2]. The cognitive impairment is mainly caused by the formation of senile plaques, which has been considered as a hallmark in the development of AD [3,4].The plaque deposits are primarily composed of insoluble fibrils that are aggregated from various amyloid-β (Aβ) peptides with 39–42 amino acids. Among these Aβ peptides, Aβ42 is an important alloform due to its high propensity for aggregation [5]. The increasing evidence indicates that the insoluble fibrillar aggregates are not the toxic species, but smaller soluble Aβ oligomers are the neurotoxic species in AD [6].
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