Tetrameric Aβ40 and Aβ42 β-Barrel Structures by Extensive Atomistic Simulations. I. In a Bilayer Mimicking a Neuronal...

Area of Science:

• Neuroscience
• Biochemistry
• Computational Biology

Background:

• Amyloid-beta (Aβ) oligomers, particularly Aβ42, are implicated in Alzheimer's disease pathogenesis.
• The amyloid pore hypothesis suggests Aβ oligomers form ion-permeable channels in neuronal membranes, contributing to toxicity.
• Experimental determination of high-resolution structures of these pore-forming oligomers is challenging due to heterogeneity.

Purpose of the Study:

• To propose atomic structures of Aβ40 and Aβ42 β-barrel oligomers within a neuronal membrane environment.
• To elucidate the structural basis for the differential toxicity between Aβ40 and Aβ42 oligomers.

Main Methods:

• Extensive atomistic simulations were employed.
• Low-resolution data from lipid bilayer experiments were integrated.
• Computational modeling and theoretical factors were utilized to derive 3D structures.

Main Results:

• Atomic structures of Aβ40 and Aβ42 β-barrels were proposed within a simulated neuronal membrane.
• The proposed 3D model features tetramer subunits, β-hairpin motifs, and an eight-antiparallel β-strand arrangement.
• The Aβ40 β-barrel structure was found to be significantly less stable than the Aβ42 counterpart.

Conclusions:

• The computational model provides insights into the structure of amyloid pores.
• The findings support the amyloid pore hypothesis in Alzheimer's disease.
• The structural destabilization of Aβ40 oligomers explains the greater neurotoxicity of Aβ42.