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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer's Disease

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Autor(es):
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Silva, Aderbal R. T. [1] ; Feio Santos, Ana Cecilia [1] ; Farfel, Jose M. [2, 3] ; Grinberg, Lea T. [2, 4] ; Ferretti, Renata E. L. [2, 3] ; Froes Marques Campos, Antonio Hugo Jose [5] ; Cunha, Isabela Werneck [5] ; Begnami, Maria Dirlei [5] ; Rocha, Rafael M. [6] ; Carraro, Dirce M. [6] ; de Braganca Pereira, Carlos Alberto [7] ; Jacob-Filho, Wilson [2, 3] ; Brentani, Helena [1]
Número total de Autores: 13
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Sch Med, Dept & Inst Psychiat, Lab Clin Pathol, Lab Med Invest 23, Sao Paulo - Brazil
[2] Univ Sao Paulo, Sch Med, LIM 22, Brazilian Brain Bank, Aging Brain Study Grp, Sao Paulo - Brazil
[3] Univ Sao Paulo, Sch Med, Div Geriatr, Sao Paulo - Brazil
[4] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA - USA
[5] AC Camargo Canc Ctr, Dept Pathol, Sao Paulo - Brazil
[6] AC Camargo Canc Ctr, Res Ctr CIPE, Sao Paulo - Brazil
[7] Univ Sao Paulo, Math & Stat Inst, Sao Paulo - Brazil
Número total de Afiliações: 7
Tipo de documento: Artigo Científico
Fonte: PLoS One; v. 9, n. 6 JUN 17 2014.
Citações Web of Science: 32
Resumo

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, p(27Kip1), 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. (AU)

Processo FAPESP: 09/01527-7 - Diferenciação entre Doença de Alzheimer sintomática e assintomática por meio da técnica de tissue microarray em cérebros humanos postmortem
Beneficiário:Aderbal Ruy Teodoro da Silva
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 09/02030-9 - Análise de danos de DNA e expressão de genes supressores de tumor em tecido post mortem de pacientes com Doença de Alzheimer
Beneficiário:Ana Cecília Feio dos Santos
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 11/01652-6 - Avaliação da Doença de Alzheimer sintomática e assintomática em cérebros humanos post-mortem
Beneficiário:Helena Paula Brentani
Linha de fomento: Auxílio à Pesquisa - Regular