Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 79, Issue -, Pages 159-173Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2019.01.027
Keywords
Interleukin-6; Neural stem cells; DNA demethylation; TET3; DNMT1; JAK2/STAT3; Alzheimer disease
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Funding
- National Natural Science Foundation of China [81371217]
- Natural Science Foundation of Guangdong [2017A030313520]
- Outstanding Young People Project of Guangdong Province [Yq2013137]
- Science and Technology Foundation of Guangdong Province [2016A020214019]
- Science and Technology Foundation of Guangzhou [201707010231]
- Science Foundation of Education Bureau of Guangzhou City [1201610239]
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Neuroinflammation, considered as a pathological hallmark of Alzheimer's disease (AD), has been demonstrated to affect hippocampal neurogenesis and cognitive function. Interleukin-6 (IL-6) is a proinflammatory cytokine known to modulate neurogenesis. However, the mechanisms are still largely unknown. Here, we reported that IL-6 suppressed neurogenesis via a JAK2/STAT3 signaling in neural stem cells (NSCs). Importantly, we found that NeuroD1 (Neurogenic differentiation 1) gene expression, which drives NSCs neurodifferentiation, was regulated by TET3 and DNMT1 in a JAK2/STAT3-dependent manner. We further found that JAK2/STAT3 inhibition enhanced demethylation of NeuroDl regulatory elements in IL-6-treated cells, which is related to the significant upregulation of TET3 expression as well as the decreased expression of DNMT1. Furthermore, Inhibiting JAK2/STAT3 significantly rescued the memory deficits and hippocampal neurogenesis dysfunction in APP/PS1 mice. Our data suggest that JAK2/STAT3 signaling plays a vital role in suppressing neurogenesis of NSCs exposed to IL-6 at the epigenetic level, by regulating DNA methylation/demethylation.
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