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

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...

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Autores principales: Silva, Aderbal R. T., Santos, Ana Cecília Feio, Farfel, Jose M., Grinberg, Lea T., Ferretti, Renata E. L., Campos, Antonio Hugo Jose Froes Marques, Cunha, Isabela Werneck, Begnami, Maria Dirlei, Rocha, Rafael M., Carraro, Dirce M., de Bragança Pereira, Carlos Alberto, Jacob-Filho, Wilson, Brentani, Helena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061071/
https://www.ncbi.nlm.nih.gov/pubmed/24936870
http://dx.doi.org/10.1371/journal.pone.0099897
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author Silva, Aderbal R. T.
Santos, Ana Cecília Feio
Farfel, Jose M.
Grinberg, Lea T.
Ferretti, Renata E. L.
Campos, Antonio Hugo Jose Froes Marques
Cunha, Isabela Werneck
Begnami, Maria Dirlei
Rocha, Rafael M.
Carraro, Dirce M.
de Bragança Pereira, Carlos Alberto
Jacob-Filho, Wilson
Brentani, Helena
author_facet Silva, Aderbal R. T.
Santos, Ana Cecília Feio
Farfel, Jose M.
Grinberg, Lea T.
Ferretti, Renata E. L.
Campos, Antonio Hugo Jose Froes Marques
Cunha, Isabela Werneck
Begnami, Maria Dirlei
Rocha, Rafael M.
Carraro, Dirce M.
de Bragança Pereira, Carlos Alberto
Jacob-Filho, Wilson
Brentani, Helena
author_sort Silva, Aderbal R. T.
collection PubMed
description 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, p27(Kip1), 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.
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spelling pubmed-40610712014-06-20 Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease Silva, Aderbal R. T. Santos, Ana Cecília Feio Farfel, Jose M. Grinberg, Lea T. Ferretti, Renata E. L. Campos, Antonio Hugo Jose Froes Marques Cunha, Isabela Werneck Begnami, Maria Dirlei Rocha, Rafael M. Carraro, Dirce M. de Bragança Pereira, Carlos Alberto Jacob-Filho, Wilson Brentani, Helena PLoS One Research Article 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, p27(Kip1), 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. Public Library of Science 2014-06-17 /pmc/articles/PMC4061071/ /pubmed/24936870 http://dx.doi.org/10.1371/journal.pone.0099897 Text en © 2014 Silva et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Silva, Aderbal R. T.
Santos, Ana Cecília Feio
Farfel, Jose M.
Grinberg, Lea T.
Ferretti, Renata E. L.
Campos, Antonio Hugo Jose Froes Marques
Cunha, Isabela Werneck
Begnami, Maria Dirlei
Rocha, Rafael M.
Carraro, Dirce M.
de Bragança Pereira, Carlos Alberto
Jacob-Filho, Wilson
Brentani, Helena
Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease
title Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease
title_full Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease
title_fullStr Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease
title_full_unstemmed Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease
title_short Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease
title_sort repair of oxidative dna damage, cell-cycle regulation and neuronal death may influence the clinical manifestation of alzheimer’s disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061071/
https://www.ncbi.nlm.nih.gov/pubmed/24936870
http://dx.doi.org/10.1371/journal.pone.0099897
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