title: Glucagon-like peptide-1 regulates mitochondrial biogenesis and tau phosphorylation against advanced glycation end product-induced neuronal insult: Studies in vivo and in vitro.
abstract: Our previous study has proved that glucagon-like peptide-1 (GLP-1), which is developed to treat type 2 diabetes, has a significant effect on neuroprotection against advanced glycation end product (AGE)-induced neuronal insult in vitro models of diabetes-related Alzheimer's disease (AD). However, the molecular mechanisms remain to be elucidated and it is not clear whether GLP-1 receptor mediates the down-regulation effects on AGE-induced AD-like changes in vivo. This study aims to explore the effect and mechanisms of GLP-1 receptor agonists (GLP-1RA) against the AGE-dependent signaling pathway both in vitro and in vivo. In this study, we demonstrated that GLP-1RA could inhibit oxidative stress and repair mitochondrial damage in addition to decreasing tau hyperphosphorylation in PC12 cells treated with AGEs. Importantly, we first observed AGEs in the circulatory system could induce tau hyperphosphorylation after we injected AGEs (1μg/kg bodyweight) into the mice tail vein. We found GLP-1RA could promote mitochondrial biogenesis and antioxidant system via regulating peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) signaling pathway in vivo besides down-regulating the activity of glycogen synthase kinase 3β (GSK-3β) to reverse tau hyperphosphorylation directly. Collectively, our results suggest that GLP-1RA protects neurons against AGE-induced tau hyperphosphorylation via regulating GSK-3β and PGC-1α two cooperative signaling pathways.
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: F-M
authors.initials: FM
authors.lastname: An
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Medical School, Southeast University, Nanjing 210009, PR China.
authors.forename: A-R
authors.initials: AR
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: wbyao@cpu.edu.cn.
authors.forename: W-B
authors.initials: WB
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: xdgao@cpu.edu.cn.
authors.forename: X-D
authors.initials: XD
authors.lastname: Gao
mesh_terms: D000818:Animals; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000633:toxicity; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D001678:Organelle Biogenesis; D016716:PC12 Cells; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D017127:Glycation End Products, Advanced; C558298:Mapt protein, mouse; C489131:Mapt protein, rat; D018696:Neuroprotective Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; D016875:tau Proteins; D052216:Glucagon-Like Peptide 1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: Mitochondrial biogenesis; advanced glycation end products; glucagon-like peptide-1; reactive oxygen species; tau pathology