Aggregation Dynamics Characteristics of Seven Different Aβ Oligomeric Isoforms-Dependence on the Interfacial...

Area of Science:

• Biochemistry
• Neuroscience
• Computational Biology

Background:

• Beta-amyloid (Aβ) peptide aggregation is a hallmark of Alzheimer's disease (AD).
• The lag phase of Aβ aggregation presents a critical window for early clinical intervention in cognitively normal individuals.
• Early-stage Aβ oligomers are neurotoxic, yet their polymorphic and metastable nature, influenced by Aβ length, poses experimental characterization challenges.

Purpose of the Study:

• To investigate the aggregation process of seven common Aβ isoforms during the lag phase using molecular dynamics simulations.
• To characterize the factors influencing the formation of stable Aβ oligomers, specifically hexamers, in the early stages of aggregation.
• To provide insights into the differential aggregation kinetics and stability of various Aβ peptide lengths.

Main Methods:

• Employed molecular dynamics simulations to model the aggregation of five monomers for each of the seven common Aβ isoforms.
• Analyzed the aggregation rates and stability of different Aβ isoforms during the lag phase.
• Investigated the role of hydrophobic interactions in the formation of stable Aβ hexamers.

Main Results:

• Aβ(1-40) and Aβ(1-38) monomers showed faster aggregation rates compared to their truncated counterparts (Aβ(4-40), Aβ(4-38)).
• Aβ(1-42) aggregation rate was slower than its truncated analogues, unlike Aβpe(3-42).
• Aβ(1-38) and Aβ(1-42) were predicted to be more likely to form stable hexamers, driven primarily by hydrophobic interactions (>50%) within interfacial β1 and β2 regions.

Conclusions:

• Aβ(1-38) and Aβ(1-42) exhibit a higher propensity for stable hexamer formation during the lag phase.
• Hydrophobic interactions, particularly within specific interfacial regions, are crucial for the stable aggregation of Aβ into higher molecular weight oligomers.
• Findings offer new perspectives on Aβ aggregation dynamics and the conditions favoring early-stage oligomer formation relevant to Alzheimer's disease pathogenesis.