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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

PPARα and PGC1α immunolocalization in the neocortex of WT and Tg mice. (a) PPARα IHC in 3-, 6-, and 18-month-old WT and Tg neocortex. Immunoreactivity levels are relatively high in Tg neurons at 3 months and show a mostly cytoplasmic localization. At 18 months, IHC intensity is lower in Tg than in WT neurons. Scale bars, 30 μm. (b) PGC1α IHC in 3-, 9-, and 18-month-old WT and Tg neocortex. Consistently low staining levels are observed in Tg neurons. Scale bars, 30 μm.
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fig6: PPARα and PGC1α immunolocalization in the neocortex of WT and Tg mice. (a) PPARα IHC in 3-, 6-, and 18-month-old WT and Tg neocortex. Immunoreactivity levels are relatively high in Tg neurons at 3 months and show a mostly cytoplasmic localization. At 18 months, IHC intensity is lower in Tg than in WT neurons. Scale bars, 30 μm. (b) PGC1α IHC in 3-, 9-, and 18-month-old WT and Tg neocortex. Consistently low staining levels are observed in Tg neurons. Scale bars, 30 μm.

Mentions: Extensive analysis of PPARα immunoreacted sections (Figure 6(a)) revealed more intense positivity in Tg neocortex than in WT at 3 months, which however decreased thereafter, becoming fainter than in WT at 18 months. Interestingly, immunostaining, especially high in pyramidal cells (according to [25]), shows a somewhat different localization depending on the age and genotype. While in WT neocortex it is first (3 months) observed in the nucleus, progressively shifting to the cytoplasm, in Tg it appears predominantly cytoplasmic since the earliest stage.


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)

PPARα and PGC1α immunolocalization in the neocortex of WT and Tg mice. (a) PPARα IHC in 3-, 6-, and 18-month-old WT and Tg neocortex. Immunoreactivity levels are relatively high in Tg neurons at 3 months and show a mostly cytoplasmic localization. At 18 months, IHC intensity is lower in Tg than in WT neurons. Scale bars, 30 μm. (b) PGC1α IHC in 3-, 9-, and 18-month-old WT and Tg neocortex. Consistently low staining levels are observed in Tg neurons. Scale bars, 30 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig6: PPARα and PGC1α immunolocalization in the neocortex of WT and Tg mice. (a) PPARα IHC in 3-, 6-, and 18-month-old WT and Tg neocortex. Immunoreactivity levels are relatively high in Tg neurons at 3 months and show a mostly cytoplasmic localization. At 18 months, IHC intensity is lower in Tg than in WT neurons. Scale bars, 30 μm. (b) PGC1α IHC in 3-, 9-, and 18-month-old WT and Tg neocortex. Consistently low staining levels are observed in Tg neurons. Scale bars, 30 μm.
Mentions: Extensive analysis of PPARα immunoreacted sections (Figure 6(a)) revealed more intense positivity in Tg neocortex than in WT at 3 months, which however decreased thereafter, becoming fainter than in WT at 18 months. Interestingly, immunostaining, especially high in pyramidal cells (according to [25]), shows a somewhat different localization depending on the age and genotype. While in WT neocortex it is first (3 months) observed in the nucleus, progressively shifting to the cytoplasm, in Tg it appears predominantly cytoplasmic since the earliest stage.

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