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

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.

Length and saturation of fatty acids in phosphatidylserine determine the rate of lysozyme aggregation simultaneously altering the structure and toxicity of amyloid oligomers and fibrils

“…One can expect that the presence of lipids on the surface of oligomers and fibrils drastically changed their interactions with the cell membranes, which ultimately lead to the observed differences in the oligomers' and fibrils' toxicity. At the same time, Zhaliazka and co‐workers recently demonstrated a direct relationship between the amount of β‐sheet and toxicity of amyloid β 1‐42 aggregates (Zhaliazka, Matveyenka, & Kurouski, 2023a). Thus, one can expect that differences in the secondary structure of amyloid aggregates determine their toxicity.…”

“…It was also found that Aβ exhibited substantially higher affinity to cholesterol compared to phospholipids, and FAs (Avdulov et al, 1997). Our own experimental results showed that lipids present in the structure of Aβ oligomers formed in their presence (Zhaliazka & Kurouski, 2023). We infer that the presence of lipids drastically changes the hydrophobic properties of oligomer surfaces facilitating their property to permeabilize plasma membranes (Matveyenka et al, 2023; Matveyenka, Rizevsky, & Kurouski, 2022a; Matveyenka, Rizevsky, & Kurouski, 2022b; Matveyenka, Zhaliazka, et al, 2022).…”

“…Similar interactions are thought to stabilize such protein‐lipid aggregates (Alza et al, 2019; Galvagnion, 2017; Giasson et al, 2001; Kiechle et al, 2020; Ueda et al, 1993). Using nano‐Infrared spectroscopy, our group demonstrated that such aggregates possessed lipids in their structure (Zhaliazka et al, 2022; Zhaliazka & Kurouski, 2023).…”

Elucidation of the Effect of Phospholipid Charge on the Rate of Insulin Aggregation and Structure and Toxicity of Amyloid Fibrils

“… 18 , 19 , 32 − 35 Thus, AFM-IR can be used to determine the chemical structure of individual protein aggregates. 26 − 31 , 33 − 37 Using AFM-IR, Rizevsky and co-workers also found that both PC and CL were found to be present in insulin oligomers that were grown in the presence of these phospholipids. 18 Independently, Matveyenka and co-workers demonstrated that the degree of saturation of FAs of both PC and CL plays an important role in insulin aggregation.…”

“…Using nanoinfrared spectroscopy, also known as atomic force microscopy infrared (AFM-IR) spectroscopy, the researchers demonstrated that insulin strongly interacts with both phosphatidylcholine (PC) and cardiolipin (CL). In AFM-IR, a metallized scanning probe is placed on the sample of interest. − Next, the sample is illuminated by pulsed tunable IR laser, which induces thermal expansions in the sample. − These expansions are recorded by the probe and converted into IR spectra. ,,− Thus, AFM-IR can be used to determine the chemical structure of individual protein aggregates. − ,− Using AFM-IR, Rizevsky and co-workers also found that both PC and CL were found to be present in insulin oligomers that were grown in the presence of these phospholipids . Independently, Matveyenka and co-workers demonstrated that the degree of saturation of FAs of both PC and CL plays an important role in insulin aggregation .…”