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Inactivation of JAK2/STAT3 signaling axis and downregulation of M1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging.

ABSTRACT: We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3) phosphorylation were observed in the hippocampus of klotho mutant mice. A selective decrease in protein expression and binding density of the M1 muscarinic cholinergic receptor (M1 mAChR) was observed in these mice. Cholinergic parameters (ie, acetylcholine (ACh), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE)) and NMDAR-dependent long-term potentiation (LTP) were significantly impaired in klotho mutant mice. McN-A-343 (McN), an M1 mAChR agonist, significantly attenuated these impairments. AG490 (AG), a JAK2 inhibitor, counteracted the attenuating effects of McN, although AG did not significantly alter the McN-induced effect on AChE. Furthermore, AG significantly inhibited the attenuating effects of McN on decreased NMDAR-dependent LTP, protein kinase C ?II, p-ERK, p-CREB, BDNF, and p-JAK2/p-STAT3-expression in klotho mutant mice. In addition, k252a, a BDNF receptor tyrosine kinase B (TrkB) inhibitor, significantly counteracted McN effects on decreased ChAT, ACh, and M1 mAChR and p-JAK2/p-STAT3 expression. McN-induced effects on cognitive impairment in klotho mutant mice were consistently counteracted by either AG or k252a. Our results suggest that inactivation of the JAK2/STAT3 signaling axis and M1 mAChR downregulation play a critical role in cognitive impairment observed in klotho mutant mice.

SUBMITTER: Park SJ

PROVIDER: S-EPMC3682136 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Inactivation of JAK2/STAT3 signaling axis and downregulation of M1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging.

Park Seok-Joo SJ Shin Eun-Joo EJ Min Sun Seek SS An Jihua J Li Zhengyi Z Hee Chung Yoon Y Hoon Jeong Ji J Bach Jae-Hyung JH Nah Seung-Yeol SY Kim Won-Ki WK Jang Choon-Gon CG Kim Yong-Sun YS Nabeshima Yo-Ichi Y Nabeshima Toshitaka T Kim Hyoung-Chun HC

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20130206 8

We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3) phosphorylation were observed in the hippocampus of klotho mutant mice. A selective decrease in protein expression and binding density of the M1 muscarinic cholinergic receptor (M1 mAChR) was observed in these mice. C ...[more]

PMID: 23389690

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Project description:BackgroundAcute pyelonephritis (APN), an acute and severe kidney infection, is usually treated with antibiotics. However, APN treatment has become increasingly challenging because of bacterial resistance. Adiponectin, an adipokine, has recently been reported to exhibit profound anti-inflammatory and anti-apoptotic effects. However, the effect of adiponectin on the outcomes of APN treatment remains unclear. In this study, we aimed to investigate the effects of adiponectin on APN and the mechanisms underlying these effects.MethodsWild-type C57 mice and adiponectin-knockout (KO) mice were divided into 6 groups: the wild-type control group, the wild-type model group, the wild-type adiponectin intervention group, the KO control group, the KO model group, and the adiponectin-KO intervention group. We measured white blood cell (WBC) and neutrophil counts (NC) using a multispecies hematology analyzer; tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) using enzyme-linked immunosorbent assay (ELISA); blood urea nitrogen (BUN) and serum creatinine (SCr) levels using colorimetry; and the protein levels of JAK2, STAT3, p-JAK2, p-STAT3, Bcl-2, and Bax in renal tissues using western blot analysis. Apoptotic cells were detected using the transferase-mediated dUTP nick end labelling (TUNEL) assay.ResultsCompared to the wild-type mice, the KO mice showed a more severe inflammatory response and kidney damage after Escherichia coli infection. After treatment with exogenous adiponectin injection, the inflammatory response, oxidative stress, and kidney damage were partly alleviated. Adiponectin KO led to JAK2/STAT3 signaling activation, and exogenous adiponectin administration inactivated JAK2/STAT3 signaling in the APN model. APN can lead to an increase in the level of the protein Bax and a decrease in the level of the bcl-2 protein, thereby increasing apoptosis; this effect was inhibited by adiponectin.ConclusionsThrough use of a pyelonephritis mouse model, we demonstrated that adiponectin might alleviate renal cell apoptosis and inflammatory response by inactivating the JAK2/STAT3 signaling pathway.

Project description:Microglia activation and associated inflammation are implicated in the periventricular white matter damage (PWMD) in septic postnatal rats. This study investigated whether melatonin would mitigate inflammation and alleviate the axonal hypomyelination in the corpus callosum in septic postnatal rats. We further explored if this might be related to the modulation of microglial polarization from M1 phenotype to M2 through the JAK2/STAT3/telomerase pathway. We reported here that indeed melatonin not only can it reduce the neurobehavioral disturbances in LPS-injected rats, but it can also dampen microglia-mediated inflammation. Thus, in LPS + melatonin group, the expression of proinflammatory mediators in M1 phenotype microglia was downregulated. As opposed to this, M2 microglia were increased which was accompanied by upregulated expression of anti-inflammatory mediators along with telomerase reverse transcriptase or melatonin receptor 1(MT1). In parallel to this was decreased NG2 expression but increased expression of myelin and neurofilament proteins. Melatonin can improve hypomyelination which was confirmed by electron microscopy. In vitro in primary microglia stimulated by LPS, melatonin decreased the expression of proinflammatory mediators significantly; but it increased the expression of anti-inflammatory mediators. Additionally, the expression levels of p-JAK2 and p-STAT3 were significantly elevated in microglia after melatonin treatment. Remarkably, the effect of melatonin on LPS-treated microglia was blocked by melatonin receptor, JAK2, STAT3 and telomerase reverse transcriptase inhibitors, respectively. Taken together, it is concluded that melatonin can attenuate PWMD through shifting M1 microglia towards M2 via MT1/JAK2/STAT3/telomerase pathway. The results suggest a new therapeutic strategy whereby melatonin may be adopted to convert microglial polarization from M1 to M2 phenotype that would ultimately contribute to the attenuation of PWMD.

Dataset Information

Inactivation of JAK2/STAT3 signaling axis and downregulation of M1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging.

Publications

Inactivation of JAK2/STAT3 signaling axis and downregulation of M1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging.

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