Lipids Uniquely Alter the Secondary Structure and Toxicity of Amyloid Beta 1-42 Aggregates

Abrupt aggregation of amyloid β (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 Aβ aggregation. However, it remains unclear whether lipids only alter rates of protein aggregation or also uniquely modify the secondary structure and toxicity of Aβ oligomers and fibrils. In this study, we investigated the effect of phosphatidylcholine (PC), cardiolipin (CL), and cholesterol (Chol) on Aβ aggregation. We found that PC, CL and Chol strongly accelerated the rate of fibril formation compared to the rate of Aβ aggregation in the lipid-free environment. Furthermore, anionic CL enabled the strongest acceleration of Aβ 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 Aβ aggregates. Specifically, CL and Chol drastically increased the amount of parallel β-sheet in Aβ 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 Aβ 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 Aβ aggregation.