Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs.
A growing body of evidence suggests type 2 diabetes mellitus (T2DM) is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanisms remain unclear, T2DM may exacerbate neurodegenerative processes. AMP-activated protein kinase (AMPK) signaling is an evolutionary preserved pathway that is important during homeostatic energy biogenesis responses at both the cellular and whole-body levels. Metformin, a ubiquitously prescribed anti-diabetic drug, exerts its effects by AMPK activation. However, while the roles of AMPK as a metabolic mediator are generally well understood, its performance in neuroprotection and neurodegeneration are not yet well defined. Given hyperglycemia is accompanied by an accelerated rate of advanced glycosylation end product (AGE) formation, which is associated with the pathogenesis of diabetic neuronal impairment and, inflammatory response, clarification of the role of AMPK signaling in these processes is needed. Therefore, we tested the hypothesis that metformin, an AMPK activator, protects against diabetic AGE induced neuronal impairment in human neural stem cells (hNSCs). In the present study, hNSCs exposed to AGE had significantly reduced cell viability, which correlated with elevated inflammatory cytokine expression, such as IL-1α, IL-1β, IL-2, IL-6, IL-12 and TNF-α. Co-treatment with metformin significantly abrogated the AGE-mediated effects in hNSCs. In addition, metformin rescued the transcript and protein expression levels of acetyl-CoA carboxylase (ACC) and inhibitory kappa B kinase (IKK) in AGE-treated hNSCs. NF-κB is a transcription factor with a key role in the expression of a variety of genes involved in inflammatory responses, and metformin did prevent the AGE-mediated increase in NF-κB mRNA and protein levels in the hNSCs exposed to AGE. Indeed, co-treatment with metformin significantly restored inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) levels in AGE-treated hNSCs. These findings extend our understanding of the central role of AMPK in AGE induced inflammatory responses, which increase the risk of neurodegeneration in diabetic patients.
Department of Internal Medicine, Cardinal Tien Hospital, College of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan.
Ming-Min
MM
Chung
Departments of Pathology & Molecular Medicine and Biomedical & Molecular Sciences, and Division of Cancer Biology & Genetics, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Christopher J
CJ
Nicol
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao Yuan 333, Taiwan.
Yi-Chuan
YC
Cheng
Graduate Institute of Biotechnology, Chinese Culture University, Taipei 111, Taiwan.
Kuan-Hung
KH
Lin
Department of Pathology, Cardinal Tien Hospital, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
Yen-Lin
YL
Chen
Department of Internal Medicine, Cardinal Tien Hospital, College of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan.
Dee
D
Pei
Department of Pediatrics, Taipei City Hospital Zhongxing Branch, Taipei 103, Taiwan.
Chien-Hung
CH
Lin
Department of Occupational Therapy, College of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan.
Yi-Nuo
YN
Shih
Department of International Business, Ming Chuan University, Taipei 111, Taiwan.
Chia-Hui
CH
Yen
Department of Life Science and Institute of Ecology and Evolutionary Biology, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
Shiang-Jiuun
SJ
Chen
Department of Entomology and Research Center for Plant-Medicine, National Taiwan University, Taipei 106, Taiwan.
Rong-Nan
RN
Huang
Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan. Electronic address: cmcphd@gmail.com.
Ming-Chang
MC
Chiang
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017127:Glycation End Products, Advanced / Q000009:adverse effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008687:Metformin / Q000494:pharmacology*; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D008687:Metformin; D055372:AMP-Activated Protein Kinases
AGE; AMPK; Inflammatory response; Metformin; hNSCs