Activation of the 5'-AMP-Activated Protein Kinase in the Cerebral Cortex of Young Senescence-Accelerated P8 Mice and Association with GSK3β- and PP2A-Dependent Inhibition of p-tau₃₉₆ Expression.
The 5'-AMP-activated protein kinase (AMPK), which is a sensor of cellular energy, regulates neuronal survival and energy homeostasis. However, the roles of AMPK in the pathogenesis of Alzheimer's disease (AD) are unclear. The senescence-accelerated mouse prone 8 (SAMP8) strain is characterized by deficits in learning and memory, exhibits pathological characteristics of AD as early as 5 months of age, and is being increasingly recognized as a model of AD. Here, we investigated the relationship between AMPK activation and phosphorylation of the tau protein in the brain of young (2-month-old) SAMP8 animals and in differentiated SH-SY5Y cells. Upregulation of p-AMPK, p-ACC, and p-GSK3βS9 and downregulation of p-tau396 and sirtuin 1 (Sirt1) were observed in the cerebral cortex of young SAMP8 mice compared with that of age-matched SAMR1 animals. The hippocampal levels of p-AMPK and p-tau396 in SAMP8 animals were not significantly different from those of SAMR1, whereas upregulation of p-GSK3βS9 and downregulation of sirt1 was observed in the hippocampus of SAMP8 mice. Consistent with in vivo findings in the cortex, AMPK activation in SH-SY5Y cells upregulated p-GSK3βS9 but downregulated p-tau396, whereas it had no significant effect on p-tau262 expression. In addition, the AMPK-mediated inhibition of p-tau396 expression was attenuated by okadaic acid, a protein phosphatase 2A (PP2A) inhibitor. Taken together, our data showed that AMPK activation inhibits p-tau396 expression in a GSK3β- and PP2A-dependent manner, and suggest that differential regulation of tau phosphorylation in young SAMP8 mice by AMPK plays a compensatory role against accelerated senescence in this AD animal model.
Department of Pharmacology and Medicinal Toxicology Research Center, Inha University, Incheon, Republic of Korea.|Hypoxia-related Diseases Research Center, College of Medicine, Inha University, Incheon, Republic of Korea.
Hak-Su
HS
Kim
Department of Pharmacology and Medicinal Toxicology Research Center, Inha University, Incheon, Republic of Korea.|Hypoxia-related Diseases Research Center, College of Medicine, Inha University, Incheon, Republic of Korea.
Sohee
S
Moon
Department of Emergency Medicine, Inha University Hospital, Incheon, Republic of Korea.
Jin-Hwe
JH
Paik
Department of Emergency Medicine, Inje University Ilsan Paik Hospital, Gyeonggi-Do, Republic of Korea.
Dong Wun
DW
Shin
College of Arts and Science, Boston College, Boston, MA, USA.
Lindsay S
LS
Kim
Department of Pharmacology and Medicinal Toxicology Research Center, Inha University, Incheon, Republic of Korea.|Hypoxia-related Diseases Research Center, College of Medicine, Inha University, Incheon, Republic of Korea.
Chang-Shin
CS
Park
Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
Joohun
J
Ha
Department of Pharmacology and Medicinal Toxicology Research Center, Inha University, Incheon, Republic of Korea.|Hypoxia-related Diseases Research Center, College of Medicine, Inha University, Incheon, Republic of Korea.
Ju-Hee
JH
Kang
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000375:Aging / Q000235:genetics / Q000473:pathology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000201:enzymology*; D005786:Gene Expression Regulation / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; D054648:Protein Phosphatase 2; D056564:Sirtuin 1
5′-AMP-activated protein kinase; GSK3β; p-tau; protein phosphatase 2A; senescence-accelerated mice; sirtuin 1; tau protein