title: Oxidative Stress during the Progression of β-Amyloid Pathology in the Neocortex of the Tg2576 Mouse Model of Alzheimer's Disease.
abstract: Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive neurodegeneration. Pathogenetic mechanisms, triggered by β-amyloid (Aβ) accumulation, include oxidative stress, derived from energy homeostasis deregulation and involving mitochondria and peroxisomes. We here addressed the oxidative stress status and the elicited cellular response at the onset and during the progression of Aβ pathology, studying the neocortex of Tg2576 model of AD. Age-dependent changes of oxidative damage markers, antioxidant enzymes, and related transcription factors were analysed in relation to the distribution of Aβ peptide and oligomers, by a combined molecular/morphological approach. Nucleic acid oxidative damage, accompanied by defective antioxidant defences, and decreased PGC1α expression are already detected in 3-month-old Tg2576 neurons. Conversely, PPARα is increased in these cells, with its cytoplasmic localization suggesting nongenomic, anti-inflammatory actions. At 6 months, when intracellular Aβ accumulates, PMP70 is downregulated, indicating impairment of fatty acids peroxisomal translocation and their consequent harmful accumulation. In 9-month-old Tg2576 neocortex, Aβ oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes. At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost. Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes.
authors.affiliation: Department of Science, LIME, University Roma Tre, Viale Guglielmo Marconi, No. 446, 00146 Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Porcellotti
authors.affiliation: Department of Science, LIME, University Roma Tre, Viale Guglielmo Marconi, No. 446, 00146 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fanelli
authors.affiliation: Department of Science, LIME, University Roma Tre, Viale Guglielmo Marconi, No. 446, 00146 Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Fracassi
authors.affiliation: Department of Science, LIME, University Roma Tre, Viale Guglielmo Marconi, No. 446, 00146 Rome, Italy ; IFOM Foundation, FIRC Institute of Molecular Oncology Foundation, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Sepe
authors.affiliation: IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64, 00143 Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.affiliation: Department of Radiological Sciences and Laboratory Medicine, UOC Pathological Anatomy, San Filippo Neri Hospital, Via Giovanni Martinotti 20, 00135 Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Bernardi
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazzale Salvatore Tommasi 1, 67100 Coppito, Italy.
authors.forename: AnnaMaria
authors.initials: A
authors.lastname: Cimini
authors.affiliation: Department of Science, LIME, University Roma Tre, Viale Guglielmo Marconi, No. 446, 00146 Rome, Italy ; Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazzale Salvatore Tommasi 1, 67100 Coppito, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Cerù
authors.affiliation: Department of Science, LIME, University Roma Tre, Viale Guglielmo Marconi, No. 446, 00146 Rome, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Moreno
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000171:Acrolein / Q000378:metabolism; D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D019579:Neocortex / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020675:Peroxisomes / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2
chemical_list: D018528:ATP-Binding Cassette Transporters; D000171:Acrolein; D016229:Amyloid beta-Peptides; D005904:Glial Fibrillary Acidic Protein; D005979:Glutathione Peroxidase; D009419:Nerve Tissue Proteins; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2; C489271:Abcd3 protein, mouse; C485290:Ppargc1a protein, mouse; C528900:glial fibrillary astrocytic protein, mouse; C000606291:Sod1 protein, mouse; C000722068:Gpx1 protein, mouse