Promotion of Amyloid β Protein Misfolding and Fibrillogenesis by a Lipid Oxidation Product

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

“…Cholesterol oxidative metabolites modify Aβ peptides by Schiff base formation leading to spherical and fibrillar Aβ aggregates (58). Lipid oxidation products promote Aβ aggregation through a pathway involving modification of His residues in Aβ proteins by Michael addition, leading to increased Aβ affinity for lipid membranes and heightened tendency for Aβ to aggregate into fibrils (59).…”

Quantitative analysis of phospholipids containing arachidonate and docosahexaenoate chains in microdissected regions of mouse brain

“…In contrast, the approach used in this work makes it reasonable to conclude, for example, that the two results for 18:1/20:4-PG in The absolute scale on which we have placed these results is only approximately accurate, for several reasons, including numerical uncertainty in the fatty acid assay results, uncertainty in assigning the fatty acid assay results to lipids from different headgroup classes that coelute, and uncertainty over whether or not signifi cant sources of AA and DHA other than phospholipid exist in each fraction. These problems could have been addressed in various ways, but addressing them would have solved only a small part of the more fundamental problem, the lack of avail- vitro data showing that an AA oxidation product (hydroxynonenal) is amyloidogenic in vitro, whereas the analogous DHA oxidation product (hydroxyhexenal) is not ( 27 ). The available data on AA and DHA levels in the brain do not clarify whether they are reduced by oxidative degradation and their oxidation products lead to neurodegenerative disease, or whether reduced levels fail to protect other substances in the brain from oxidative damage.…”

“…However, not all models or protocols have found DHA to have a benefi cial effect ( 25,26 ). In contrast to the amyloidogenicity of an AA oxidation product, the corresponding oxidation product of DHA is not amyloidogenic ( 27 ).…”

Oxidative Stress and Neurodegenerative Disease

“…The loss of redox homeostasis, both endogenous or exogenous, produces a state of chronic oxidative stress that increases the production of ROS and RNS, causes a reduced expression or activity of antioxidant systems, accelerates ageing, and plays a key role in the pathogenesis and the course of Alzheimer's disease by the altering of many signaling metabolic pathways in the cell by promoting mutations or altering the postransductional mechanisms. The chronic disruption of the oxidation-reduction balance, causes bad protein folding, products of advanced glycosylation, overload of peroxidation of saturated fatty acids (hydroxynonenal, HNE) (Liu, 2008), oxidation of cholesterol, disturbances in the insulin receptor to cause insulin resistance, and oxidation of LDL receptors involved in the reentry of peptide or the APP (Liu, 2008). We can infer that Alzheimer's is the final manifestation of a series of oxidative alterations of metabolism, which involve different biomolecules, in which the loss of the oxide-reduction balance plays a decisive role in the formation of the phosphorylated tau protein and insoluble beta amyloid .…”