title: Repair of oxidative DNA damage, cell-cycle regulation and neuronal death may influence the clinical manifestation of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by progressive cognitive decline associated with a featured neuropathology (neuritic plaques and neurofibrillary tangles). Several studies have implicated oxidative damage to DNA, DNA repair, and altered cell-cycle regulation in addition to cell death in AD post-mitotic neurons. However, there is a lack of studies that systematically assess those biological processes in patients with AD neuropathology but with no evidence of cognitive impairment. We evaluated markers of oxidative DNA damage (8-OHdG, H2AX), DNA repair (p53, BRCA1, PTEN), and cell-cycle (Cdk1, Cdk4, Cdk5, Cyclin B1, Cyclin D1, p27Kip1, phospho-Rb and E2F1) through immunohistochemistry and cell death through TUNEL in autopsy hippocampal tissue samples arrayed in a tissue microarray (TMA) composed of three groups: I) "clinical-pathological AD" (CP-AD)--subjects with neuropathological AD (Braak ≥ IV and CERAD = B or C) and clinical dementia (CDR ≥ 2, IQCODE>3.8); II) "pathological AD" (P-AD)--subjects with neuropathological AD (Braak ≥ IV and CERAD = B or C) and without cognitive impairment (CDR 0, IQCODE<3.2); and III) "normal aging" (N)--subjects without neuropathological AD (Braak ≤ II and CERAD 0 or A) and with normal cognitive function (CDR 0, IQCODE<3.2). Our results show that high levels of oxidative DNA damage are present in all groups. However, significant reductions in DNA repair and cell-cycle inhibition markers and increases in cell-cycle progression and cell death markers in subjects with CP-AD were detected when compared to both P-AD and N groups, whereas there were no significant differences in the studied markers between P-AD individuals and N subjects. This study indicates that, even in the setting of pathological AD, healthy cognition may be associated with a preserved repair to DNA damage, cell-cycle regulation, and cell death in post-mitotic neurons.
authors.affiliation: Laboratory of Clinical Pathology - Laboratory of Medical Investigations 23 (LIM 23), Department and Institute of Psychiatry, University of São Paulo, Medical School, São Paulo, Brazil.
authors.forename: Aderbal R T
authors.initials: AR
authors.lastname: Silva
authors.affiliation: Laboratory of Clinical Pathology - Laboratory of Medical Investigations 23 (LIM 23), Department and Institute of Psychiatry, University of São Paulo, Medical School, São Paulo, Brazil.
authors.forename: Ana Cecília Feio
authors.initials: AC
authors.lastname: Santos
authors.affiliation: Brazilian Brain Bank of the Aging Brain Study Group - Laboratory of Medical Investigations 22 (LIM 22), University of São Paulo, Medical School, São Paulo, Brazil; Division of Geriatrics, University of São Paulo, Medical School, São Paulo, Brazil.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Farfel
authors.affiliation: Brazilian Brain Bank of the Aging Brain Study Group - Laboratory of Medical Investigations 22 (LIM 22), University of São Paulo, Medical School, São Paulo, Brazil; Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Lea T
authors.initials: LT
authors.lastname: Grinberg
authors.affiliation: Brazilian Brain Bank of the Aging Brain Study Group - Laboratory of Medical Investigations 22 (LIM 22), University of São Paulo, Medical School, São Paulo, Brazil; Division of Geriatrics, University of São Paulo, Medical School, São Paulo, Brazil.
authors.forename: Renata E L
authors.initials: RE
authors.lastname: Ferretti
authors.affiliation: Department of Pathology, A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Antonio Hugo Jose Froes Marques
authors.initials: AH
authors.lastname: Campos
authors.affiliation: Department of Pathology, A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Isabela Werneck
authors.initials: IW
authors.lastname: Cunha
authors.affiliation: Department of Pathology, A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Maria Dirlei
authors.initials: MD
authors.lastname: Begnami
authors.affiliation: Research Center (CIPE), A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Rocha
authors.affiliation: Research Center (CIPE), A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Dirce M
authors.initials: DM
authors.lastname: Carraro
authors.affiliation: Mathematics and Statistics Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: de Bragança Pereira
authors.affiliation: Brazilian Brain Bank of the Aging Brain Study Group - Laboratory of Medical Investigations 22 (LIM 22), University of São Paulo, Medical School, São Paulo, Brazil; Division of Geriatrics, University of São Paulo, Medical School, São Paulo, Brazil.
authors.forename: Wilson
authors.initials: W
authors.lastname: Jacob-Filho
authors.affiliation: Laboratory of Clinical Pathology - Laboratory of Medical Investigations 23 (LIM 23), Department and Institute of Psychiatry, University of São Paulo, Medical School, São Paulo, Brazil.
authors.forename: Helena
authors.initials: H
authors.lastname: Brentani
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis; D002453:Cell Cycle; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D009474:Neurons / Q000502:physiology*; D018384:Oxidative Stress; D046888:Tissue Array Analysis; D059467:Transcriptome