FynT tyrosine kinase facilitated TNF-induced inflammatory response in astrocytes: relevant to chronic neuroinflammation in Alzheimer's disease
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1
Singapore General Hospital, Department of Clinical Translational Research, Singapore
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2
Yong Loo Lin School of Medicine, National University of Singapore, Department of Pharmacology, Singapore
Fyn tyrosine kinase is implicated in the pathogenesis of Alzheimer's disease (AD). We have previously demonstrated that FynT but not the brain predominant FynB isoform was significantly up-regulated in AD brains and independently associated with neurofibrillary degeneration and reactive astrogliosis. In this study, we aimed to characterize the functional role of FynT in astrocytes. First, FynT expression was shown to be positively correlated with astrocytic markers in mixed cortical culture with increased astrocytic population. Furthermore, rat primary astrocytes treated with tumour necrosis factor (TNF) demonstrated selectively increase of FynT but no change of FynB expression, suggesting that FynT may be involved in astrocytic proinflammatory signaling. To determine the functional role of FynT, immortalized normal human astrocytes (iNHA) stably expressing FynT mutants with kinase constitutively active (FynT-CA) or kinase dead (FynT-KD) were treated with TNF and monitored for inflammatory response up to 3 days. iNHA bearing FynT-CA mutant displayed proactive in the expression and release of cytokine and chemokine at day 3 of TNF treatment in comparison with FynT-KD mutant and vector control, as determined using high-throughput real-time RT-PCR and luminex multi-analyte immunoassay. Furthermore, FynT tyrosine kinase activity facilitated pro-inflammatory response under prolonged exposure to TNF, likely through NF-kappaB signaling pathway. Specific silencing of FynT expression or treating with Src kinase inhibitor PP2 in FynT-CA cells further confirmed that FynT kinase activity was required for modulating TNF-induced inflammatory response. Our study demonstrated that selective up-regulation of astrocytic FynT expression in AD may be associated with chronic neuroinflammation during the disease progression.
Keywords:
Astrocytes,
neurodegeneration,
Alzheimer’s disease,
Neuroinflammation,
Signalling pathway
Conference:
14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016.
Presentation Type:
Poster Presentation Session
Topic:
14th Meeting of the Asian-Pacific Society for Neurochemistry
Citation:
Lee
CL,
Low
CY,
Lai
MK and
Tan
MG
(2016). FynT tyrosine kinase facilitated TNF-induced inflammatory response in astrocytes: relevant to chronic neuroinflammation in Alzheimer's disease.
Conference Abstract:
14th Meeting of the Asian-Pacific Society for Neurochemistry.
doi: 10.3389/conf.fncel.2016.36.00154
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Received:
04 Aug 2016;
Published Online:
11 Aug 2016.
*
Correspondence:
Dr. Michelle G Tan, Singapore General Hospital, Department of Clinical Translational Research, Singapore, Singapore, Singapore, michelle.tan.g.k@sgh.com.sg