Elucidation of molecular mechanisms by which amyloid β1–42 fibrils exert cell toxicity

Abrupt aggregation of amyloid β_1–42 (Aβ_1–42) peptide in the frontal lobe is the expected underlying cause of Alzheimer's disease (AD). β-Sheet-rich oligomers and fibrils formed by Aβ_1–42 exert high cell toxicity. A growing body of evidence indicates that lipids can uniquely alter the secondary structure and toxicity of Aβ_1–42 aggregates. At the same time, underlying molecular mechanisms that determine this difference in toxicity of amyloid aggregates remain unclear. Using a set of molecular and biophysical assays to determine the molecular mechanism by which Aβ_1–42 aggregates formed in the presence of cholesterol, cardiolipin, and phosphatidylcholine exert cell toxicity. Our findings demonstrate that rat neuronal cells exposed to Aβ_1–42 fibrils formed in the presence of lipids with different chemical structure exert drastically different magnitude and dynamic of unfolded protein response (UPR) in the endoplasmic reticulum (ER) and mitochondria (MT). We found that the opposite dynamics of UPR in MT and ER in the cells exposed to Aβ_1–42: cardiolipin fibrils and Aβ_1–42 aggregates formed in a lipid-free environment. We also found that Aβ_1–42: phosphatidylcholine fibrils upregulated ER UPR simultaneously downregulating the UPR response of MT, whereas Aβ_1–42: cholesterol fibrils suppressed the UPR response of ER and upregulated UPR response of MT. We also observed progressively increasing ROS production that damages mitochondrial membranes and other cell organelles, ultimately leading to cell death.