title: Hydroxynonenal-generated crosslinking fluorophore accumulation in Alzheimer disease reveals a dichotomy of protein turnover.
abstract: Lipid peroxidation generates reactive aldehydes, most notably hydroxynonenal (HNE), which covalently bind amino acid residue side chains leading to protein inactivation and insolubility. Specific adducts of lipid peroxidation have been demonstrated in intimate association with the pathological lesions of Alzheimer disease (AD), suggesting that oxidative stress is a major component of AD pathogenesis. Some HNE-protein products result in protein crosslinking through a fluorescent compound similar to lipofuscin, linking lipid peroxidation and the lipofuscin accumulation that commonly occurs in post-mitotic cells such as neurons. In this study, brain tissue from AD and control patients was examined by immunocytochemistry and immunoelectron microscopy for evidence of HNE-crosslinking modifications of the type that should accumulate in the lipofuscin pathway. Strong labeling of granulovacuolar degeneration (GVD) and Hirano bodies was noted but lipofuscin did not contain this specific HNE-fluorophore. These findings directly implicate lipid crosslinking peroxidation products as accumulating not in the lesions or the lipofuscin pathways, but instead in a distinct pathway, GVD, that accumulates cytosolic proteins.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA. Electronic address: xiongwei.zhu@case.edu.
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pathology, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Castellani
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Paula I
authors.initials: PI
authors.lastname: Moreira
authors.affiliation: Institute for Neuroscience, University of Texas at San Antonio, San Antonio, Texas, USA.
authors.forename: Gjumrakch
authors.initials: G
authors.lastname: Aliev
authors.affiliation: Institute for Neuroscience, University of Texas at San Antonio, San Antonio, Texas, USA.
authors.forename: Justin C
authors.initials: JC
authors.lastname: Shenk
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Siedlak
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Peggy L R
authors.initials: PLR
authors.lastname: Harris
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujioka
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Sayre
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Szweda
authors.affiliation: Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Luke I
authors.initials: LI
authors.lastname: Szweda
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Institute for Neuroscience, University of Texas at San Antonio, San Antonio, Texas, USA. Electronic address: george.perry@utsa.edu.
authors.forename: George
authors.initials: G
authors.lastname: Perry
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000447:Aldehydes / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D003594:Cytoplasmic Granules / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015227:Lipid Peroxidation; D008062:Lipofuscin / Q000378:metabolism; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational
chemical_list: D000447:Aldehydes; D008062:Lipofuscin; D009419:Nerve Tissue Proteins; C027576:4-hydroxy-2-nonenal