Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013:2013:606083.
doi: 10.1155/2013/606083. Epub 2013 Sep 23.

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

Ethika Tyagi  1 , Tina Fiorelli, Michelle Norden, Jaya Padmanabhan
Affiliations

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

Ethika Tyagi et al. Int J Alzheimers Dis. 2013.

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Tau hyperphosphorylation in ACT expressing mice: cortex and hippocampal regions from normal nontransgenic (mTau), ACT expressing (ACT/mTau), human tau expressing (hTau), and both ACT and hTau expressing (ACT/mTau/hTau) mice were analyzed for changes in phosphorylation of tau at PHF-1 (a), p-Ser202 (b), pThr231 (c) specific epitopes, and total tau (d) using the corresponding P-tau or the TG5 total tau antibody by western blot and quantified using the Image J image analysis software. The data shows significant increase in P-tau levels in ACT and hTau as well as the double transgenic ACT/hTau mice (*P < 0.05). Only P-Ser202 tau showed significant change in double transgenic mice compared to mice expressing hTau alone (# P < 0.05).
Figure 2
Figure 2
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.
Figure 3
Figure 3
Inflammatory proteins induce tau phosphorylation through JNK activation: JNK phosphorylation in different brain regions—hippocampus (a), cerebral cortex (b), and striatum (c), in mTau, ACT/mTau and ACT/mTau/hTau mice injected with aCSF and IL-1β (1 ng/10 μL) *P < 0.05 (aCSF versus IL-1β treated group). Values are 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.
Figure 4
Figure 4
ACT-mediated tau phosphorylation at p-Ser202, p-Thr231, PHF-1, and p-Ser262 in cortical neurons is inhibited by JNK inhibitor: mouse cortical neurons were cultured in 8-chamber slides and preincubated with JNK Inhibitor (10 μM, 1 hour). The cells were then treated with or without 1 mg/mL ACT for 8 hours and probed with (a) p-Ser202 tau monoclonal and p-Thr231 tau polyclonal, (b) PHF-1 tau monoclonal and P-Ser262 tau polyclonal antibodies. Anti-mouse Alexa fluor 488 (green) and anti-rabbit Alexa Flour 594 (red) were used as secondary antibodies, and Hoechst was used to visualize the nuclei. Staining was visualized under a Zeiss fluorescent microscope and analyzed using AxioVision Rel. 4.8 software.
Figure 5
Figure 5
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Silverman GA, Bird PI, Carrell RW, et al. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. Journal of Biological Chemistry. 2001;276(36):33293–33296. - PubMed
    1. Kalsheker NA. α1-antichymotrypsin. International Journal of Biochemistry and Cell Biology. 1996;28(9):961–964. - PubMed
    1. Licastro F, Mallory M, Hansen LA, Masliah E. Increased levels of α-1-antichymotrypsin in brains of patients with Alzheimer’s disease correlate with activated astrocytes and are affected by APOE 4 genotype. Journal of Neuroimmunology. 1998;88(1-2):105–110. - PubMed
    1. Abraham CR, Selkoe DJ, Potter H. Immunochemical identification of the serine protease inhibitor α1-antichymotrypsin in the brain amyloid deposits of Alzheimer’s disease. Cell. 1988;52(4):487–501. - PubMed
    1. Licastro F, Parnetti L, Morini MC, et al. Acute phase reactant α1-antichymotrypsin is increased in cerebrospinal fluid and serum of patients with probable Alzheimer disease. Alzheimer Disease and Associated Disorders. 1995;9(2):112–118. - PubMed