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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

Peroxisomal protein levels and distribution in the neocortex of WT and Tg mice. PMP70 expression showing downregulation at 6 months, as assessed by WB densitometry (a) and IHC distribution (b). Enhancement of PMP70 expression is observed in 9-month-old Tg neurons. Scale bars, 40 μm. (c) Densitometric analyses of WB for CAT, Pex14p, AOX, and THL performed on neocortical protein extracts from 3-, 6-, 9-, 12-, and 18-month-old mice. Significant downregulation of CAT in 6-month-old Tg neocortex is detected. Values are expressed as mean ± SD. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001.
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fig9: Peroxisomal protein levels and distribution in the neocortex of WT and Tg mice. PMP70 expression showing downregulation at 6 months, as assessed by WB densitometry (a) and IHC distribution (b). Enhancement of PMP70 expression is observed in 9-month-old Tg neurons. Scale bars, 40 μm. (c) Densitometric analyses of WB for CAT, Pex14p, AOX, and THL performed on neocortical protein extracts from 3-, 6-, 9-, 12-, and 18-month-old mice. Significant downregulation of CAT in 6-month-old Tg neocortex is detected. Values are expressed as mean ± SD. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001.

Mentions: Data obtained by WB and IHC on peroxisomal proteins are reported in Figure 9. While no age- or genotype-based differences of protein levels are detected for CAT, Pex14p, AOX, or THL, significant variations are observed for PMP70. This protein, involved in the transport of long and methyl-branched acyl-CoA esthers [26, 27] across the peroxisomal membrane, is highly expressed at 3 months in both genotypes and significantly downregulated at 6 months, particularly in the Tg neocortex, where the protein is almost reduced by half. A novel increase is observed in 9-month-old Tg, and these levels are maintained thereafter.


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)

Peroxisomal protein levels and distribution in the neocortex of WT and Tg mice. PMP70 expression showing downregulation at 6 months, as assessed by WB densitometry (a) and IHC distribution (b). Enhancement of PMP70 expression is observed in 9-month-old Tg neurons. Scale bars, 40 μm. (c) Densitometric analyses of WB for CAT, Pex14p, AOX, and THL performed on neocortical protein extracts from 3-, 6-, 9-, 12-, and 18-month-old mice. Significant downregulation of CAT in 6-month-old Tg neocortex is detected. Values are expressed as mean ± SD. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig9: Peroxisomal protein levels and distribution in the neocortex of WT and Tg mice. PMP70 expression showing downregulation at 6 months, as assessed by WB densitometry (a) and IHC distribution (b). Enhancement of PMP70 expression is observed in 9-month-old Tg neurons. Scale bars, 40 μm. (c) Densitometric analyses of WB for CAT, Pex14p, AOX, and THL performed on neocortical protein extracts from 3-, 6-, 9-, 12-, and 18-month-old mice. Significant downregulation of CAT in 6-month-old Tg neocortex is detected. Values are expressed as mean ± SD. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001.
Mentions: Data obtained by WB and IHC on peroxisomal proteins are reported in Figure 9. While no age- or genotype-based differences of protein levels are detected for CAT, Pex14p, AOX, or THL, significant variations are observed for PMP70. This protein, involved in the transport of long and methyl-branched acyl-CoA esthers [26, 27] across the peroxisomal membrane, is highly expressed at 3 months in both genotypes and significantly downregulated at 6 months, particularly in the Tg neocortex, where the protein is almost reduced by half. A novel increase is observed in 9-month-old Tg, and these levels are maintained thereafter.

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