title: Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against Amyloid-beta-induced mitochondrial dysfunction.
abstract: Alzheimer's disease (AD) is the general consequence of dementia and is diagnostic neuropathology by the cumulation of amyloid-beta (Aβ) protein aggregates, which are thought to promote mitochondrial dysfunction processes leading to neurodegeneration. AMP-activated protein kinase (AMPK), a critical regulator of energy homeostasis and a major player in lipid and glucose metabolism, is potentially implied in the mitochondrial deficiency of AD. Metformin, one of the widespread used anti- metabolic disease drugs, use its actions in part by stimulation of AMPK. While the mechanisms of AD are well established, the neuronal roles for AMPK in AD are still not well understood. In the present study, human neural stem cells (hNSCs) exposed to Aβ had significantly reduced cell viability, which correlated with decreased AMPK, neuroprotective genes (Bcl-2 and CREB) and mitochondria associated genes (PGC1α, NRF-1 and Tfam) expressions, as well as increased activation of caspase 3/9 activity and cytosolic cytochrome c. Co-treatment with metformin distinct abolished the Aβ-caused actions in hNSCs. Metformin also significantly rescued hNSCs from Aβ-mediated mitochondrial deficiency (lower D-loop level, mitochondrial mass, maximal respiratory function, COX activity, and mitochondrial membrane potential). Importantly, co-treatment with metformin significantly restored fragmented mitochondria to almost normal morphology in the hNSCs with Aβ. These findings extend our understanding of the central role of AMPK in Aβ-related neuronal impairment. Thus, a better understanding of AMPK might assist in both the recognition of its critical effects and the implementation of new therapeutic strategies in the treatment of AD.
authors.affiliation: Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan. Electronic address: cmcphd@gmail.com.
authors.forename: Ming-Chang
authors.initials: MC
authors.lastname: Chiang
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yi-Chuan
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: Department of Life Science and Institute of Ecology and Evolutionary Biology, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Shiang-Jiuun
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Department of International Business, Ming Chuan University, Taipei 111, Taiwan.
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Yen
authors.affiliation: Department of Entomology and Research Center for Plant-Medicine, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Rong-Nan
authors.initials: RN
authors.lastname: Huang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008687:Metformin / Q000378:metabolism* / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D045304:Cytochromes c; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Aβ; HNSCs; Mitochondrial function; PGC1α