Trapping and Characterization of Nontoxic Aβ42 Aggregation Intermediates

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Amyloid beta (Aβ) 42 is a key peptide in Alzheimer's disease (AD) pathogenesis.
• Aβ42 aggregation, particularly diffusible oligomers, is linked to neurotoxicity.
• Age-related molecular changes can alter protein behavior.

Purpose of the Study:

• To investigate the impact of Ser26 epimerization (S26s) in Aβ42 on aggregation and toxicity.
• To elucidate the structural mechanisms underlying the effects of S26s substitution.

Main Methods:

• Biophysical and biochemical assays to study Aβ42 aggregation.
• Nuclear Magnetic Resonance (NMR) spectroscopy.
• Density Functional Theory (DFT) computational modeling.

Main Results:

• S26s substitution in Aβ42 reduced fibril formation propensity.
• The resulting soluble aggregates of Aβ42-S26s were found to be non-toxic.
• NMR and DFT studies revealed local structural changes and the formation of an intramolecular Ser26-Asn27 H-bond.
• This H-bond disrupted the intermolecular Asn27 side chain interactions crucial for aggregation.

Conclusions:

• Age-related epimerization of Ser26 in Aβ42 significantly alters its aggregation pathway.
• The S26s modification yields non-toxic soluble aggregates by preventing key intermolecular interactions.
• Intermolecular Asn27 side chain interactions are critical determinants of Aβ42 aggregation and associated toxicity.