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Oxidative Stress during the Progression of β-Amyloid Pathology in the Neocortex of the Tg2576 Mouse Model of Alzheimer's Disease.

Porcellotti S, Fanelli F, Fracassi A, Sepe S, Cecconi F, Bernardi C, Cimini A, Cerù MP, Moreno S - Oxid Med Cell Longev (2015)

Bottom Line: In 9-month-old Tg2576 neocortex, Aβ oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes.At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost.Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes.

View Article: PubMed Central - PubMed

Affiliation: Department of Science, LIME, University Roma Tre, Viale Guglielmo Marconi, No. 446, 00146 Rome, Italy.

ABSTRACT
Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive neurodegeneration. Pathogenetic mechanisms, triggered by β-amyloid (Aβ) accumulation, include oxidative stress, derived from energy homeostasis deregulation and involving mitochondria and peroxisomes. We here addressed the oxidative stress status and the elicited cellular response at the onset and during the progression of Aβ pathology, studying the neocortex of Tg2576 model of AD. Age-dependent changes of oxidative damage markers, antioxidant enzymes, and related transcription factors were analysed in relation to the distribution of Aβ peptide and oligomers, by a combined molecular/morphological approach. Nucleic acid oxidative damage, accompanied by defective antioxidant defences, and decreased PGC1α expression are already detected in 3-month-old Tg2576 neurons. Conversely, PPARα is increased in these cells, with its cytoplasmic localization suggesting nongenomic, anti-inflammatory actions. At 6 months, when intracellular Aβ accumulates, PMP70 is downregulated, indicating impairment of fatty acids peroxisomal translocation and their consequent harmful accumulation. In 9-month-old Tg2576 neocortex, Aβ oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes. At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost. Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes.

No MeSH data available.


Related in: MedlinePlus

GPX1 expression and distribution in WT and Tg neocortex. GPX1 shows a strongly age- and genotype-related IHC pattern (a) consistent with WB densitometric data (b). Higher expression levels at 9 months and lower levels at 3 and 18 months are detected in Tg neocortex, as compared to WT. Values are expressed as mean ± SD. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001. The higher magnification micrograph (c) shows elevated immunoreactivity in glial cells surrounding and infiltrating an amyloid plaque of 18-month-old Tg neocortex. Scale bars, 40 μm.
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fig8: GPX1 expression and distribution in WT and Tg neocortex. GPX1 shows a strongly age- and genotype-related IHC pattern (a) consistent with WB densitometric data (b). Higher expression levels at 9 months and lower levels at 3 and 18 months are detected in Tg neocortex, as compared to WT. Values are expressed as mean ± SD. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001. The higher magnification micrograph (c) shows elevated immunoreactivity in glial cells surrounding and infiltrating an amyloid plaque of 18-month-old Tg neocortex. Scale bars, 40 μm.

Mentions: In both genotypes, GPX1 shows an age-related pattern characterized by progressive increase of protein levels from youth to maturity, followed by a decrease to minimal values in senescence (Figure 8). This pattern appears exacerbated in Tg neocortex, where the protein is downregulated with respect to WT at 3 months, overexpressed at 9 months, and again downregulated at 18 months, when immunostaining is almost exclusively concentrated at the senile plaques.


Oxidative Stress during the Progression of β-Amyloid Pathology in the Neocortex of the Tg2576 Mouse Model of Alzheimer's Disease.

Porcellotti S, Fanelli F, Fracassi A, Sepe S, Cecconi F, Bernardi C, Cimini A, Cerù MP, Moreno S - Oxid Med Cell Longev (2015)

GPX1 expression and distribution in WT and Tg neocortex. GPX1 shows a strongly age- and genotype-related IHC pattern (a) consistent with WB densitometric data (b). Higher expression levels at 9 months and lower levels at 3 and 18 months are detected in Tg neocortex, as compared to WT. Values are expressed as mean ± SD. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001. The higher magnification micrograph (c) shows elevated immunoreactivity in glial cells surrounding and infiltrating an amyloid plaque of 18-month-old Tg neocortex. Scale bars, 40 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig8: GPX1 expression and distribution in WT and Tg neocortex. GPX1 shows a strongly age- and genotype-related IHC pattern (a) consistent with WB densitometric data (b). Higher expression levels at 9 months and lower levels at 3 and 18 months are detected in Tg neocortex, as compared to WT. Values are expressed as mean ± SD. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001. The higher magnification micrograph (c) shows elevated immunoreactivity in glial cells surrounding and infiltrating an amyloid plaque of 18-month-old Tg neocortex. Scale bars, 40 μm.
Mentions: In both genotypes, GPX1 shows an age-related pattern characterized by progressive increase of protein levels from youth to maturity, followed by a decrease to minimal values in senescence (Figure 8). This pattern appears exacerbated in Tg neocortex, where the protein is downregulated with respect to WT at 3 months, overexpressed at 9 months, and again downregulated at 18 months, when immunostaining is almost exclusively concentrated at the senile plaques.

Bottom Line: In 9-month-old Tg2576 neocortex, Aβ oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes.At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost.Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes.

View Article: PubMed Central - PubMed

Affiliation: Department of Science, LIME, University Roma Tre, Viale Guglielmo Marconi, No. 446, 00146 Rome, Italy.

ABSTRACT
Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive neurodegeneration. Pathogenetic mechanisms, triggered by β-amyloid (Aβ) accumulation, include oxidative stress, derived from energy homeostasis deregulation and involving mitochondria and peroxisomes. We here addressed the oxidative stress status and the elicited cellular response at the onset and during the progression of Aβ pathology, studying the neocortex of Tg2576 model of AD. Age-dependent changes of oxidative damage markers, antioxidant enzymes, and related transcription factors were analysed in relation to the distribution of Aβ peptide and oligomers, by a combined molecular/morphological approach. Nucleic acid oxidative damage, accompanied by defective antioxidant defences, and decreased PGC1α expression are already detected in 3-month-old Tg2576 neurons. Conversely, PPARα is increased in these cells, with its cytoplasmic localization suggesting nongenomic, anti-inflammatory actions. At 6 months, when intracellular Aβ accumulates, PMP70 is downregulated, indicating impairment of fatty acids peroxisomal translocation and their consequent harmful accumulation. In 9-month-old Tg2576 neocortex, Aβ oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes. At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost. Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes.

No MeSH data available.


Related in: MedlinePlus