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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

Schematic showing the inflammation-associated mechanisms in tau phosphorylation and tangle formation in brain: environmental factors, injury to brain, or enhanced inflammation induce Aβ generation as well as microglial activation which leads to increased generation of IL-1β (cytokine) which in turn has been shown to enhance ACT expression. ACT has been shown to induce tau hyperphosphorylation through activation of GSK-3αβ, or ERK (earlier studies) or JNK (data presented here). This may lead to enhanced tangle formation and neurodegeneration. ACT already has been shown to enhance Aβ aggregation and accelerated plaque formation, whether it enhances tau aggregation and tangle formation needs to be determined.
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fig5: Schematic showing the inflammation-associated mechanisms in tau phosphorylation and tangle formation in brain: environmental factors, injury to brain, or enhanced inflammation induce Aβ generation as well as microglial activation which leads to increased generation of IL-1β (cytokine) which in turn has been shown to enhance ACT expression. ACT has been shown to induce tau hyperphosphorylation through activation of GSK-3αβ, or ERK (earlier studies) or JNK (data presented here). This may lead to enhanced tangle formation and neurodegeneration. ACT already has been shown to enhance Aβ aggregation and accelerated plaque formation, whether it enhances tau aggregation and tangle formation needs to be determined.

Mentions: The results from our studies presented here show that the inflammatory protein ACT induces tau hyperphosphorylation through activation of JNK. Earlier in vitro studies from our laboratory have shown that ACT enhances tau hyperphosphorylation through activation of GSK-3αβ and ERK [23]. Figure 5 shows a schematic depicting the pathway that may be involved in ACT-induced neurodegeneration in AD. Since ACT expression is significantly upregulated in AD brain, we believe that it plays a major role in tangle formation by participating in upregulation of kinases involved in tau hyperphosphorylation in neurons. Thus, these studies suggest that a better understanding of the signaling mechanisms involved in inflammation-mediated tau hyperphosphorylation may lead to more effective anti-inflammatory therapeutic strategies for preventing or treating AD neurodegeneration associated with chronic inflammation.


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)

Schematic showing the inflammation-associated mechanisms in tau phosphorylation and tangle formation in brain: environmental factors, injury to brain, or enhanced inflammation induce Aβ generation as well as microglial activation which leads to increased generation of IL-1β (cytokine) which in turn has been shown to enhance ACT expression. ACT has been shown to induce tau hyperphosphorylation through activation of GSK-3αβ, or ERK (earlier studies) or JNK (data presented here). This may lead to enhanced tangle formation and neurodegeneration. ACT already has been shown to enhance Aβ aggregation and accelerated plaque formation, whether it enhances tau aggregation and tangle formation needs to be determined.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Schematic showing the inflammation-associated mechanisms in tau phosphorylation and tangle formation in brain: environmental factors, injury to brain, or enhanced inflammation induce Aβ generation as well as microglial activation which leads to increased generation of IL-1β (cytokine) which in turn has been shown to enhance ACT expression. ACT has been shown to induce tau hyperphosphorylation through activation of GSK-3αβ, or ERK (earlier studies) or JNK (data presented here). This may lead to enhanced tangle formation and neurodegeneration. ACT already has been shown to enhance Aβ aggregation and accelerated plaque formation, whether it enhances tau aggregation and tangle formation needs to be determined.
Mentions: The results from our studies presented here show that the inflammatory protein ACT induces tau hyperphosphorylation through activation of JNK. Earlier in vitro studies from our laboratory have shown that ACT enhances tau hyperphosphorylation through activation of GSK-3αβ and ERK [23]. Figure 5 shows a schematic depicting the pathway that may be involved in ACT-induced neurodegeneration in AD. Since ACT expression is significantly upregulated in AD brain, we believe that it plays a major role in tangle formation by participating in upregulation of kinases involved in tau hyperphosphorylation in neurons. Thus, these studies suggest that a better understanding of the signaling mechanisms involved in inflammation-mediated tau hyperphosphorylation may lead to more effective anti-inflammatory therapeutic strategies for preventing or treating AD neurodegeneration associated with chronic inflammation.

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