title: Oxidative stress and lipid peroxidation are upstream of amyloid pathology.
abstract: Oxidative stress is a common feature of the aging process and of many neurodegenerative disorders, including Alzheimer's disease. Understanding the direct causative relationship between oxidative stress and amyloid pathology, and determining the underlying molecular mechanisms is crucial for the development of more effective therapeutics for the disease. By employing microdialysis technique, we report local increase in the amyloid-β42 levels and elevated amyloid-β42/40 ratio in the interstitial fluid within 6h of direct infusion of oxidizing agents into the hippocampus of living and awake wild type mice. The increase in the amyloid-β42/40 ratio correlated with the pathogenic conformational change of the amyloid precursor protein-cleaving enzyme, presenilin1/γ-secretase. Furthermore, we found that the product of lipid peroxidation 4-hydroxynonenal, binds to both nicastrin and BACE, differentially affecting γ- and β-secretase activity, respectively. The present study demonstrates a direct cause-and-effect correlation between oxidative stress and altered amyloid-β production, and provides a molecular mechanism by which naturally occurring product of lipid peroxidation may trigger generation of toxic amyloid-β42 species.
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, CNY 114, 16th Street, Charlestown 02129, MA, USA.
authors.forename: Muriel
authors.initials: M
authors.lastname: Arimon
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, CNY 114, 16th Street, Charlestown 02129, MA, USA.
authors.forename: Shuko
authors.initials: S
authors.lastname: Takeda
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, CNY 114, 16th Street, Charlestown 02129, MA, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Post
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, CNY 114, 16th Street, Charlestown 02129, MA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Svirsky
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, CNY 114, 16th Street, Charlestown 02129, MA, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, CNY 114, 16th Street, Charlestown 02129, MA, USA. Electronic address: OBerezovska@partners.org.
authors.forename: Oksana
authors.initials: O
authors.lastname: Berezovska
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000447:Aldehydes / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004220:Disulfides / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism
chemical_list: D000447:Aldehydes; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D004220:Disulfides; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D053764:Presenilin-1; D011725:Pyridines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C413604:nicastrin protein; C580804:presenilin 1, mouse; C007542:4,4'-dipyridyl disulfide; C487056:N-Acetylcysteinamide; D053829:Amyloid Precursor Protein Secretases; C027576:4-hydroxy-2-nonenal; D000111:Acetylcysteine
keywords: 4-Hydroxynonenal; Alzheimer's disease; Amyloid beta; Lipid peroxidation; Microdialysis; Oxidative stress; Presenilin; γ-Secretase