A2T and A2V Aβ peptides exhibit different aggregation kinetics, primary nucleation, morphology, structure, and LTP inhibition

Proteins
Brian MurrayGeorges Belfort

Abstract

The histopathological hallmark of Alzheimer's disease (AD) is the aggregation and accumulation of the amyloid beta peptide (Aβ) into misfolded oligomers and fibrils. Here we examine the biophysical properties of a protective Aβ variant against AD, A2T, and a causative mutation, A2T, along with the wild type (WT) peptide. The main finding here is that the A2V native monomer is more stable than both A2T and WT, and this manifests itself in different biophysical behaviors: the kinetics of aggregation, the initial monomer conversion to an aggregation prone state (primary nucleation), the abundances of oligomers, and extended conformations. Aggregation reaction modeling of the conversion kinetics from native monomers to fibrils predicts the enhanced stability of the A2V monomer, while ion mobility spectrometry-mass spectrometry measures this directly confirming earlier predictions. Additionally, unique morphologies of the A2T aggregates are observed using atomic force microscopy, providing a basis for the reduction in long term potentiation inhibition of hippocampal cells for A2T compared with A2V and the wild type (WT) peptide. The stability difference of the A2V monomer and the difference in aggregate morphology for A2T (both comp...Continue Reading

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Citations

Dec 23, 2016·Physical Chemistry Chemical Physics : PCCP·Son Tung NgoMinh Tho Nguyen
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Feb 12, 2017·ACS Chemical Neuroscience·Brian MurrayGeorges Belfort
May 29, 2018·ACS Central Science·Payel DasJeetain Mittal

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