Lipids uniquely alter the secondary structure and toxicity of amyloid beta 1–42 aggregates

Author:

Zhaliazka Kiryl1,Matveyenka Mikhail1,Kurouski Dmitry12ORCID

Affiliation:

1. Department of Biochemistry and Biophysics Texas A&M University College Station Texas USA

2. Department of Biomedical Engineering Texas A&M University College Station Texas USA

Abstract

Abrupt aggregation of amyloid β1‐42 (Aβ) peptide is a hallmark of Alzheimer's disease (AD), a severe pathology that affects more than 44 million people worldwide. A growing body of evidence suggests that lipids can uniquely alter rates of Aβ1‐42 aggregation. However, it remains unclear whether lipids only alter rates of protein aggregation or also uniquely modify the secondary structure and toxicity of Aβ1‐42 oligomers and fibrils. In this study, we investigated the effect of phosphatidylcholine (PC), cardiolipin (CL), and cholesterol (Chol) on Aβ1‐42 aggregation. We found that PC, CL and Chol strongly accelerated the rate of fibril formation compared to the rate of Aβ1‐42 aggregation in the lipid‐free environment. Furthermore, anionic CL enabled the strongest acceleration of Aβ1‐42 aggregation compared to zwitterionic PC and uncharged Chol. We also found that PC, CL and Chol uniquely altered the secondary structure of early‐, middle‐ and late‐stage Aβ1‐42 aggregates. Specifically, CL and Chol drastically increased the amount of parallel β‐sheet in Aβ1‐42 oligomers and fibrils grown in the presence of these lipids. This caused a significant increase in the toxicity of Aβ : CL and Aβ : Chol compared to the toxicity of Aβ : PC and Aβ1‐42 aggregates formed in the lipid‐free environment. These results demonstrate that toxicity of Aβ aggregates correlates with the amount of their β‐sheet content, which, in turn, is determined by the chemical structure of lipids present at the stage of Aβ1‐42 aggregation.

Funder

National Institute of General Medical Sciences

Publisher

Wiley

Subject

Cell Biology,Molecular Biology,Biochemistry

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