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Repair of oxidative DNA damage, cell-cycle regulation and neuronal death may influence the clinical manifestation of Alzheimer's disease.

Silva AR, Santos AC, Farfel JM, Grinberg LT, Ferretti RE, Campos AH, Cunha IW, Begnami MD, Rocha RM, Carraro DM, de Bragança Pereira CA, Jacob-Filho W, Brentani H - PLoS ONE (2014)

Bottom Line: Alzheimer's disease (AD) is characterized by progressive cognitive decline associated with a featured neuropathology (neuritic plaques and neurofibrillary tangles).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.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.

View Article: PubMed Central - PubMed

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.

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.

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Hierarchical clustering analysis of CP-AD, P-AD and N samples.Hierarchical clustering was performed by using the expression values from the markers with differential expression between CP-AD and P-AD/N. Each row represents a single marker, and each column represents a sample. Red indicates high expression, and green indicates low expression. The cluster support was performed with the Bootstrap technique (black, 100% support; grey, 90–100%; blue, 80–90%; green, 70–80%; light yellow, 60–70%; dark yellow, 50–60%; magenta, 0–50%, red, 0%). CP-AD, clinical-pathological Alzheimer’s disease; P-AD, pathological Alzheimer’s disease; N, normal aging.
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pone-0099897-g006: Hierarchical clustering analysis of CP-AD, P-AD and N samples.Hierarchical clustering was performed by using the expression values from the markers with differential expression between CP-AD and P-AD/N. Each row represents a single marker, and each column represents a sample. Red indicates high expression, and green indicates low expression. The cluster support was performed with the Bootstrap technique (black, 100% support; grey, 90–100%; blue, 80–90%; green, 70–80%; light yellow, 60–70%; dark yellow, 50–60%; magenta, 0–50%, red, 0%). CP-AD, clinical-pathological Alzheimer’s disease; P-AD, pathological Alzheimer’s disease; N, normal aging.

Mentions: Searching for an expression pattern based on markers that achieved statistical significance between the CP-AD group and the other two groups (P-AD and N), a hierarchical clustering was conducted with all individuals in this study. The dendrogram in Figure 6 shows a sample discrimination pattern, with 100% support, in two clusters: 1) CP-AD cluster, which grouped all CP-AD samples; and 2) P-AD + N cluster, which grouped individuals with P-AD and individuals with normal aging.


Repair of oxidative DNA damage, cell-cycle regulation and neuronal death may influence the clinical manifestation of Alzheimer's disease.

Silva AR, Santos AC, Farfel JM, Grinberg LT, Ferretti RE, Campos AH, Cunha IW, Begnami MD, Rocha RM, Carraro DM, de Bragança Pereira CA, Jacob-Filho W, Brentani H - PLoS ONE (2014)

Hierarchical clustering analysis of CP-AD, P-AD and N samples.Hierarchical clustering was performed by using the expression values from the markers with differential expression between CP-AD and P-AD/N. Each row represents a single marker, and each column represents a sample. Red indicates high expression, and green indicates low expression. The cluster support was performed with the Bootstrap technique (black, 100% support; grey, 90–100%; blue, 80–90%; green, 70–80%; light yellow, 60–70%; dark yellow, 50–60%; magenta, 0–50%, red, 0%). CP-AD, clinical-pathological Alzheimer’s disease; P-AD, pathological Alzheimer’s disease; N, normal aging.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061071&req=5

pone-0099897-g006: Hierarchical clustering analysis of CP-AD, P-AD and N samples.Hierarchical clustering was performed by using the expression values from the markers with differential expression between CP-AD and P-AD/N. Each row represents a single marker, and each column represents a sample. Red indicates high expression, and green indicates low expression. The cluster support was performed with the Bootstrap technique (black, 100% support; grey, 90–100%; blue, 80–90%; green, 70–80%; light yellow, 60–70%; dark yellow, 50–60%; magenta, 0–50%, red, 0%). CP-AD, clinical-pathological Alzheimer’s disease; P-AD, pathological Alzheimer’s disease; N, normal aging.
Mentions: Searching for an expression pattern based on markers that achieved statistical significance between the CP-AD group and the other two groups (P-AD and N), a hierarchical clustering was conducted with all individuals in this study. The dendrogram in Figure 6 shows a sample discrimination pattern, with 100% support, in two clusters: 1) CP-AD cluster, which grouped all CP-AD samples; and 2) P-AD + N cluster, which grouped individuals with P-AD and individuals with normal aging.

Bottom Line: Alzheimer's disease (AD) is characterized by progressive cognitive decline associated with a featured neuropathology (neuritic plaques and neurofibrillary tangles).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.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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus