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Effect of p62 on tau hyperphosphorylation in a rat model of Alzheimer's disease.

Zheng X, Wang W, Liu R, Huang H, Zhang R, Sun L - Neural Regen Res (2012)

Bottom Line: However, whether p62 participates in oxidative stress-induced tau hyperphosphorylation remains unclear.The number of neurons in the brain decreased in Alzheimer's disease rats, and the autophagy related proteins Atg12-Atg5, microtubule-associated protein 1 light chain 3-phosphatidylethanolamine and Beclin1 increased significantly, while p62 expression reduced.Expression of kelch-like ECH-associated protein 1 increased, NF-E2-related factor 2 protein and the downstream gene products of glutamate cysteine ligase catalytic subunit and glutamate cysteine ligase modulatory subunit decreased, and hyperphosphorylated tau increased.

View Article: PubMed Central - PubMed

Affiliation: Department of Cytobiology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, Jilin Province, China.

ABSTRACT
Tau hyperphosphorylation is a main cause of neuronal loss in Alzheimer's disease, which can be caused by many factors, including oxidative stress. The multifunctional protein p62, which exists in neurofibrillary tangles and causes aggregation of hyperphosphorylated tau, not only serves as a receptor in selective autophagy, but also regulates oxidative stress. However, whether p62 participates in oxidative stress-induced tau hyperphosphorylation remains unclear. In this study, we produced an Alzheimer's disease rat model by injecting β-amyloid protein into the hippocampus and β-galactose intraperitoneally. Hematoxylin-eosin staining was used for morphological analysis of brain tissue, and western blotting, immunohistochemistry and reverse transcription-PCR were employed to study p62 and autophagy related proteins, antioxidant defense system kelch-like ECH-associated protein 1-NF-E2-related factor 2 related proteins and hyperphosphorylated tau, respectively. The number of neurons in the brain decreased in Alzheimer's disease rats, and the autophagy related proteins Atg12-Atg5, microtubule-associated protein 1 light chain 3-phosphatidylethanolamine and Beclin1 increased significantly, while p62 expression reduced. Expression of kelch-like ECH-associated protein 1 increased, NF-E2-related factor 2 protein and the downstream gene products of glutamate cysteine ligase catalytic subunit and glutamate cysteine ligase modulatory subunit decreased, and hyperphosphorylated tau increased. These findings demonstrate that autophagy levels increased and p62 levels decreased in the brains of Alzheimer's disease rats. Moreover, the anti-oxidative capability of the NF-E2-related factor 2-antioxidant response element pathway was decreased, which may be the cause of tau hyperphosphorylation in Alzheimer's disease brain tissue and the subsequent structural and functional damage to neurons.

No MeSH data available.


Related in: MedlinePlus

Changes in Keap1 and Nrf2 expression in the rat cerebral cortex and hippocampus.(A, B) Immunohistochemical and quantitative analysis for the expression of Keap1 in the cerebral cortex of Alzheimer's disease (AD) model rats. The expression of Keap1 in AD model rats was increased compared with the control (CON) group.(C, D) Immunohistochemical and quantitative analysis for the expression of Nrf2 in the cerebral cortex of AD model rats. The expression of Nrf2 in AD model rats increased compared with control rats.(E, F) Immunohistochemical and quantitative analysis for the expression of Keap1 in the hippocampus of AD model rats. The expression of Keap1 in AD model rats increased compared with control rats.(G, H) Immunohistochemical and quantitative analysis for the expression of Nrf2 in the hippocampus of AD model rats. The expression of Nrf2 in AD model rats remained unchanged compared with control rats.Scale bars: 20 μm. aP < 0.05, vs. control rats (one-way analysis of variance followed by Dunnett's t-test). The assay was performed three times and data were expressed as mean ± SD.Nrf2: NF-E2-related factor 2; Keap1: kelch-like ECH-associated protein 1.
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Figure 3: Changes in Keap1 and Nrf2 expression in the rat cerebral cortex and hippocampus.(A, B) Immunohistochemical and quantitative analysis for the expression of Keap1 in the cerebral cortex of Alzheimer's disease (AD) model rats. The expression of Keap1 in AD model rats was increased compared with the control (CON) group.(C, D) Immunohistochemical and quantitative analysis for the expression of Nrf2 in the cerebral cortex of AD model rats. The expression of Nrf2 in AD model rats increased compared with control rats.(E, F) Immunohistochemical and quantitative analysis for the expression of Keap1 in the hippocampus of AD model rats. The expression of Keap1 in AD model rats increased compared with control rats.(G, H) Immunohistochemical and quantitative analysis for the expression of Nrf2 in the hippocampus of AD model rats. The expression of Nrf2 in AD model rats remained unchanged compared with control rats.Scale bars: 20 μm. aP < 0.05, vs. control rats (one-way analysis of variance followed by Dunnett's t-test). The assay was performed three times and data were expressed as mean ± SD.Nrf2: NF-E2-related factor 2; Keap1: kelch-like ECH-associated protein 1.

Mentions: Immunohistochemical staining results (Figure 3) showed that the expression of Keap1 in the cerebral cortex and hippocampus of AD model rats increased significantly when compared with control rats (P < 0.05).


Effect of p62 on tau hyperphosphorylation in a rat model of Alzheimer's disease.

Zheng X, Wang W, Liu R, Huang H, Zhang R, Sun L - Neural Regen Res (2012)

Changes in Keap1 and Nrf2 expression in the rat cerebral cortex and hippocampus.(A, B) Immunohistochemical and quantitative analysis for the expression of Keap1 in the cerebral cortex of Alzheimer's disease (AD) model rats. The expression of Keap1 in AD model rats was increased compared with the control (CON) group.(C, D) Immunohistochemical and quantitative analysis for the expression of Nrf2 in the cerebral cortex of AD model rats. The expression of Nrf2 in AD model rats increased compared with control rats.(E, F) Immunohistochemical and quantitative analysis for the expression of Keap1 in the hippocampus of AD model rats. The expression of Keap1 in AD model rats increased compared with control rats.(G, H) Immunohistochemical and quantitative analysis for the expression of Nrf2 in the hippocampus of AD model rats. The expression of Nrf2 in AD model rats remained unchanged compared with control rats.Scale bars: 20 μm. aP < 0.05, vs. control rats (one-way analysis of variance followed by Dunnett's t-test). The assay was performed three times and data were expressed as mean ± SD.Nrf2: NF-E2-related factor 2; Keap1: kelch-like ECH-associated protein 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4308800&req=5

Figure 3: Changes in Keap1 and Nrf2 expression in the rat cerebral cortex and hippocampus.(A, B) Immunohistochemical and quantitative analysis for the expression of Keap1 in the cerebral cortex of Alzheimer's disease (AD) model rats. The expression of Keap1 in AD model rats was increased compared with the control (CON) group.(C, D) Immunohistochemical and quantitative analysis for the expression of Nrf2 in the cerebral cortex of AD model rats. The expression of Nrf2 in AD model rats increased compared with control rats.(E, F) Immunohistochemical and quantitative analysis for the expression of Keap1 in the hippocampus of AD model rats. The expression of Keap1 in AD model rats increased compared with control rats.(G, H) Immunohistochemical and quantitative analysis for the expression of Nrf2 in the hippocampus of AD model rats. The expression of Nrf2 in AD model rats remained unchanged compared with control rats.Scale bars: 20 μm. aP < 0.05, vs. control rats (one-way analysis of variance followed by Dunnett's t-test). The assay was performed three times and data were expressed as mean ± SD.Nrf2: NF-E2-related factor 2; Keap1: kelch-like ECH-associated protein 1.
Mentions: Immunohistochemical staining results (Figure 3) showed that the expression of Keap1 in the cerebral cortex and hippocampus of AD model rats increased significantly when compared with control rats (P < 0.05).

Bottom Line: However, whether p62 participates in oxidative stress-induced tau hyperphosphorylation remains unclear.The number of neurons in the brain decreased in Alzheimer's disease rats, and the autophagy related proteins Atg12-Atg5, microtubule-associated protein 1 light chain 3-phosphatidylethanolamine and Beclin1 increased significantly, while p62 expression reduced.Expression of kelch-like ECH-associated protein 1 increased, NF-E2-related factor 2 protein and the downstream gene products of glutamate cysteine ligase catalytic subunit and glutamate cysteine ligase modulatory subunit decreased, and hyperphosphorylated tau increased.

View Article: PubMed Central - PubMed

Affiliation: Department of Cytobiology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, Jilin Province, China.

ABSTRACT
Tau hyperphosphorylation is a main cause of neuronal loss in Alzheimer's disease, which can be caused by many factors, including oxidative stress. The multifunctional protein p62, which exists in neurofibrillary tangles and causes aggregation of hyperphosphorylated tau, not only serves as a receptor in selective autophagy, but also regulates oxidative stress. However, whether p62 participates in oxidative stress-induced tau hyperphosphorylation remains unclear. In this study, we produced an Alzheimer's disease rat model by injecting β-amyloid protein into the hippocampus and β-galactose intraperitoneally. Hematoxylin-eosin staining was used for morphological analysis of brain tissue, and western blotting, immunohistochemistry and reverse transcription-PCR were employed to study p62 and autophagy related proteins, antioxidant defense system kelch-like ECH-associated protein 1-NF-E2-related factor 2 related proteins and hyperphosphorylated tau, respectively. The number of neurons in the brain decreased in Alzheimer's disease rats, and the autophagy related proteins Atg12-Atg5, microtubule-associated protein 1 light chain 3-phosphatidylethanolamine and Beclin1 increased significantly, while p62 expression reduced. Expression of kelch-like ECH-associated protein 1 increased, NF-E2-related factor 2 protein and the downstream gene products of glutamate cysteine ligase catalytic subunit and glutamate cysteine ligase modulatory subunit decreased, and hyperphosphorylated tau increased. These findings demonstrate that autophagy levels increased and p62 levels decreased in the brains of Alzheimer's disease rats. Moreover, the anti-oxidative capability of the NF-E2-related factor 2-antioxidant response element pathway was decreased, which may be the cause of tau hyperphosphorylation in Alzheimer's disease brain tissue and the subsequent structural and functional damage to neurons.

No MeSH data available.


Related in: MedlinePlus