Lipids uniquely alter the secondary structure and toxicity of amyloid beta 1-42 aggregates.
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abstract
Abrupt aggregation of amyloid 1-42 (A) peptide is a hallmark of Alzheimer's disease (AD), a severe pathology that affects more than 44million people worldwide. A growing body of evidence suggests that lipids can uniquely alter rates of A1-42 aggregation. However, it remains unclear whether lipids only alter rates of protein aggregation or also uniquely modify the secondary structure and toxicity of A1-42 oligomers and fibrils. In this study, we investigated the effect of phosphatidylcholine (PC), cardiolipin (CL), and cholesterol (Chol) on A1-42 aggregation. We found that PC, CL and Chol strongly accelerated the rate of fibril formation compared to the rate of A1-42 aggregation in the lipid-free environment. Furthermore, anionic CL enabled the strongest acceleration of A1-42 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 A1-42 aggregates. Specifically, CL and Chol drastically increased the amount of parallel -sheet in A1-42 oligomers and fibrils grown in the presence of these lipids. This caused a significant increase in the toxicity of A:CL and A:Chol compared to the toxicity of A:PC and A1-42 aggregates formed in the lipid-free environment. These results demonstrate that toxicity of A aggregates correlates with the amount of their -sheet content, which, in turn, is determined by the chemical structure of lipids present at the stage of A1-42 aggregation.
