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Alpha 1-Antichymotrypsin, an Inflammatory Protein Overexpressed in the Brains of Patients with Alzheimer's Disease, Induces Tau Hyperphosphorylation through c-Jun N-Terminal Kinase Activation.

Tyagi E, Fiorelli T, Norden M, Padmanabhan J - Int J Alzheimers Dis (2013)

Bottom Line: Later studies from our laboratory have shown that purified ACT induces tau hyperphosphorylation and degeneration in neurons.We verified the involvement of JNK in ACT-induced tau phosphorylation by utilizing JNK inhibitors in cultured primary neurons treated with ACT, and we found that the inhibitor showed complete prevention of ACT-induced tau phosphorylation.These results indicate that JNK is one of the major kinases involved in the ACT-mediated tau hyperphosphorylation and suggest that inhibitors of this kinase may protect against inflammation-induced tau hyperphosphorylation and neurodegeneration associated with AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine, University of South Florida, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA ; USF Health Byrd Alzheimer's Institute, University of South Florida, 4001 E. Fletcher Avenue, Tampa, FL 33613, USA.

ABSTRACT
The association of inflammatory proteins with neuritic plaques in the brains of Alzheimer's disease (AD) patients has led to the hypothesis that inflammation plays a pivotal role in the development of pathology in AD. Earlier studies have shown that alpha 1-antichymotrypsin (ACT) enhances amyloid beta fibrillization and accelerated plaque formation in APP transgenic mice. Later studies from our laboratory have shown that purified ACT induces tau hyperphosphorylation and degeneration in neurons. In order to understand the mechanisms by which inflammatory proteins enhance tau hyperphosphorylation, we injected interleukin-1 β (IL-1 β ) intracerebroventricularly into mice expressing human ACT, human tau, or both transgenes. It was found that the hyperphosphorylation of tau in ACT and ACT/htau mice after IL-1 β injection correlated with increased phosphorylation of c-Jun N-terminal kinase (JNK). We verified the involvement of JNK in ACT-induced tau phosphorylation by utilizing JNK inhibitors in cultured primary neurons treated with ACT, and we found that the inhibitor showed complete prevention of ACT-induced tau phosphorylation. These results indicate that JNK is one of the major kinases involved in the ACT-mediated tau hyperphosphorylation and suggest that inhibitors of this kinase may protect against inflammation-induced tau hyperphosphorylation and neurodegeneration associated with AD.

No MeSH data available.


Related in: MedlinePlus

Inflammatory proteins induce tau hyperphosphorylation in AD-associated regions in the brain: PHF-1 and p-Ser202 Tau phosphorylation in different brain regions—hippocampus (a), cerebral cortex (b), and striatum (c) from control mice (mTau), and mouse expressing ACT/mTau and ACT/mTau/hTau transgenes injected with CSF and IL-1β (1 ng/10 μL) *P < 0.05, **P < 0.01 (calculated from aCSF versus IL-1β treated group). Values were normalized to actin levels. The blot above each bar graph shows a representative western blot showing corresponding P-tau in the samples from different mice. The data was collected from four independent mice from each genotype group.
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fig2: Inflammatory proteins induce tau hyperphosphorylation in AD-associated regions in the brain: PHF-1 and p-Ser202 Tau phosphorylation in different brain regions—hippocampus (a), cerebral cortex (b), and striatum (c) from control mice (mTau), and mouse expressing ACT/mTau and ACT/mTau/hTau transgenes injected with CSF and IL-1β (1 ng/10 μL) *P < 0.05, **P < 0.01 (calculated from aCSF versus IL-1β treated group). Values were normalized to actin levels. The blot above each bar graph shows a representative western blot showing corresponding P-tau in the samples from different mice. The data was collected from four independent mice from each genotype group.

Mentions: The data shown in Figures 2 and 3 were analyzed using a two-way analysis of variance (ANOVA), with genotype and treatment as the independent variables. Post-hoc analysis was performed using a Fisher's protected Least Significant Difference test to compare IL-1β treated animals with aCSF-injected animals within each genotype. Data shown in Figure 1 was analyzed using Student's t-test. A P value of <0.05 was considered statistically significant.


Alpha 1-Antichymotrypsin, an Inflammatory Protein Overexpressed in the Brains of Patients with Alzheimer's Disease, Induces Tau Hyperphosphorylation through c-Jun N-Terminal Kinase Activation.

Tyagi E, Fiorelli T, Norden M, Padmanabhan J - Int J Alzheimers Dis (2013)

Inflammatory proteins induce tau hyperphosphorylation in AD-associated regions in the brain: PHF-1 and p-Ser202 Tau phosphorylation in different brain regions—hippocampus (a), cerebral cortex (b), and striatum (c) from control mice (mTau), and mouse expressing ACT/mTau and ACT/mTau/hTau transgenes injected with CSF and IL-1β (1 ng/10 μL) *P < 0.05, **P < 0.01 (calculated from aCSF versus IL-1β treated group). Values were normalized to actin levels. The blot above each bar graph shows a representative western blot showing corresponding P-tau in the samples from different mice. The data was collected from four independent mice from each genotype group.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3794555&req=5

fig2: Inflammatory proteins induce tau hyperphosphorylation in AD-associated regions in the brain: PHF-1 and p-Ser202 Tau phosphorylation in different brain regions—hippocampus (a), cerebral cortex (b), and striatum (c) from control mice (mTau), and mouse expressing ACT/mTau and ACT/mTau/hTau transgenes injected with CSF and IL-1β (1 ng/10 μL) *P < 0.05, **P < 0.01 (calculated from aCSF versus IL-1β treated group). Values were normalized to actin levels. The blot above each bar graph shows a representative western blot showing corresponding P-tau in the samples from different mice. The data was collected from four independent mice from each genotype group.
Mentions: The data shown in Figures 2 and 3 were analyzed using a two-way analysis of variance (ANOVA), with genotype and treatment as the independent variables. Post-hoc analysis was performed using a Fisher's protected Least Significant Difference test to compare IL-1β treated animals with aCSF-injected animals within each genotype. Data shown in Figure 1 was analyzed using Student's t-test. A P value of <0.05 was considered statistically significant.

Bottom Line: Later studies from our laboratory have shown that purified ACT induces tau hyperphosphorylation and degeneration in neurons.We verified the involvement of JNK in ACT-induced tau phosphorylation by utilizing JNK inhibitors in cultured primary neurons treated with ACT, and we found that the inhibitor showed complete prevention of ACT-induced tau phosphorylation.These results indicate that JNK is one of the major kinases involved in the ACT-mediated tau hyperphosphorylation and suggest that inhibitors of this kinase may protect against inflammation-induced tau hyperphosphorylation and neurodegeneration associated with AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine, University of South Florida, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA ; USF Health Byrd Alzheimer's Institute, University of South Florida, 4001 E. Fletcher Avenue, Tampa, FL 33613, USA.

ABSTRACT
The association of inflammatory proteins with neuritic plaques in the brains of Alzheimer's disease (AD) patients has led to the hypothesis that inflammation plays a pivotal role in the development of pathology in AD. Earlier studies have shown that alpha 1-antichymotrypsin (ACT) enhances amyloid beta fibrillization and accelerated plaque formation in APP transgenic mice. Later studies from our laboratory have shown that purified ACT induces tau hyperphosphorylation and degeneration in neurons. In order to understand the mechanisms by which inflammatory proteins enhance tau hyperphosphorylation, we injected interleukin-1 β (IL-1 β ) intracerebroventricularly into mice expressing human ACT, human tau, or both transgenes. It was found that the hyperphosphorylation of tau in ACT and ACT/htau mice after IL-1 β injection correlated with increased phosphorylation of c-Jun N-terminal kinase (JNK). We verified the involvement of JNK in ACT-induced tau phosphorylation by utilizing JNK inhibitors in cultured primary neurons treated with ACT, and we found that the inhibitor showed complete prevention of ACT-induced tau phosphorylation. These results indicate that JNK is one of the major kinases involved in the ACT-mediated tau hyperphosphorylation and suggest that inhibitors of this kinase may protect against inflammation-induced tau hyperphosphorylation and neurodegeneration associated with AD.

No MeSH data available.


Related in: MedlinePlus