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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: PLoS One; v. 9, n. 6 JUN 17 2014.
• Web of Science Citations: 32

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, 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)

• FAPESP's process: 11/01652-6 - Evaluation of symptomatic and asymptomatic Alzheimer's Disease in post-mortem human brains
• Grantee: Helena Paula Brentani
• Support Opportunities: Regular Research Grants
• FAPESP's process: 09/02030-9 - Analysis of DNA damage and expression of tumor suppressor genes in post mortem tissue of patients with Alzheimer's disease
• Grantee: Ana Cecília Feio dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 09/01527-7 - Differentiation between symptomatic and non symptomatic Alzheimer's Disease through the tissue microarray technique in postmortem human brains
• Grantee: Aderbal Ruy Teodoro da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate