Chronological changes in the expression of phosphorylated tau and 5‑AMP‑activated protein kinase in the brain of senescence‑accelerated P8 mice.

Senescence-accelerated mouse prone 8 (SAMP8), a non‑transgenic animal model used for researching sporadic Alzheimer's disease (AD), presents AD pathologies and overall dysregulation in brain energy metabolism, which is one of the early pathogenic characteristics of AD. In the present study, the authors examined chronological changes in the expression patterns of phosphorylated tau and of proteins related to energy metabolism to evaluate the association of tau phosphorylation and metabolism, using young‑ (2‑months‑old), middle‑ (5‑months‑old) and old‑aged (10‑months‑old) SAMP8. The levels of phosphorylated 5'‑AMP activated protein kinase at Thr172 (p‑AMPK) and phosphorylated glycogen synthase kinase 3β (p‑GSK3βS9) in the cortex of SAMP8 at 2 months were significantly higher than those in senescence‑accelerated mouse resistant 1 (SAMR1). The differences were not detected at 5 and 10 months of age, which were concurrent with the changes in levels of phosphorylated tau at Ser396 (p‑tauS396), but not with p‑tauS262. The level of p‑tauS262 was considerably higher in the cortex of middle‑aged SAMP8 when compared with that of SAMR1 and sustained in old‑aged SAMP8, but not in the young cortex. The levels of cortical sirtuin1 (Sirt1) and insulin receptor substrate 1 (IRS‑1) expression of young SAMP8 were significantly lower, when compared with those in SAMR1. However, in the hippocampus of SAMP8, the patterns of chronological changes and levels of p‑tau, p‑AMPK, Sirt1 and IRS‑1 relative to SAMR1 were different from those in the cortex. Taken together, the results suggested that regulation of tau phosphorylation via the AMPK‑GSK3β pathway concurrent with dysregulation of energy metabolism may precede the pathological tau hyperphosphorylation in the cortex of SAMP8, and that the regulation of AMPK‑GSK3β‑mediated tau phosphorylation may be dependent on phosphor‑epitope in tau or the region of brain.

[1]  T. Lai,et al.  Amyloid-β suppresses AMP-activated protein kinase (AMPK) signaling and contributes to α-synuclein-induced cytotoxicity , 2016, Experimental Neurology.

[2]  G. Biessels,et al.  Hippocampal insulin resistance and cognitive dysfunction , 2015, Nature Reviews Neuroscience.

[3]  Hung‐wen Liu,et al.  Dietary (-)-Epigallocatechin-3-gallate Supplementation Counteracts Aging-Associated Skeletal Muscle Insulin Resistance and Fatty Liver in Senescence-Accelerated Mouse. , 2015, Journal of agricultural and food chemistry.

[4]  E. Feldman,et al.  Insulin Resistance Prevents AMPK-induced Tau Dephosphorylation through Akt-mediated Increase in AMPKSer-485 Phosphorylation* , 2015, The Journal of Biological Chemistry.

[5]  D. Hardie.  AMPK--sensing energy while talking to other signaling pathways. , 2014, Cell metabolism.

[6]  William B. Mair,et al.  AMPK at the nexus of energetics and aging. , 2014, Cell metabolism.

[7]  C. Kahn,et al.  Insulin Action in Brain Regulates Systemic Metabolism and Brain Function , 2014, Diabetes.

[8]  S. M. de la Monte,et al.  Brain metabolic dysfunction at the core of Alzheimer's disease. , 2014, Biochemical pharmacology.

[9]  M. Xilouri,et al.  The protective role of AMP-activated protein kinase in alpha-synuclein neurotoxicity in vitro , 2014, Neurobiology of Disease.

[10]  S. Ramamurthy,et al.  AMPK activation regulates neuronal structure in developing hippocampal neurons , 2014, Neuroscience.

[11]  Bin Zhang,et al.  Distinct α-Synuclein Strains Differentially Promote Tau Inclusions in Neurons , 2013, Cell.

[12]  David Carling,et al.  AMPK, insulin resistance, and the metabolic syndrome. , 2013, The Journal of clinical investigation.

[13]  E. Vara,et al.  Melatonin can improve insulin resistance and aging-induced pancreas alterations in senescence-accelerated prone male mice (SAMP8) , 2013, AGE.

[14]  K. Chan,et al.  Adiponectin is Protective against Oxidative Stress Induced Cytotoxicity in Amyloid-Beta Neurotoxicity , 2012, PloS one.

[15]  J. Morley,et al.  The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer's disease. , 2012, Biochimica et biophysica acta.

[16]  J. Morley,et al.  The SAMP8 mouse: a model to develop therapeutic interventions for Alzheimer's disease. , 2012, Current pharmaceutical design.

[17]  Yu-mi Jang,et al.  AMPK activation inhibits apoptosis and tau hyperphosphorylation mediated by palmitate in SH-SY5Y cells , 2011, Brain Research.

[18]  J. Prehn,et al.  Role of 5'-adenosine monophosphate-activated protein kinase in cell survival and death responses in neurons. , 2011, Antioxidants & redox signaling.

[19]  David Carling,et al.  AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid β-peptide exposure. , 2011, The Biochemical journal.

[20]  D. Dickson,et al.  AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies , 2011, Acta Neuropathologica.

[21]  P. Davies,et al.  Novel synthetic small‐molecule activators of AMPK as enhancers of autophagy and amyloid‐β peptide degradation , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  Zhiyong Cheng,et al.  Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK Pathways , 2010, Molecular and Cellular Biology.

[23]  N. Ruderman,et al.  AMPK and SIRT1: a long-standing partnership? , 2010, American journal of physiology. Endocrinology and metabolism.

[24]  Rosemary O’Connor,et al.  Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling , 2010, Neurobiology of Aging.

[25]  Steven J. Greco,et al.  Leptin inhibits glycogen synthase kinase-3β to prevent tau phosphorylation in neuronal cells , 2009, Neuroscience Letters.

[26]  Huaxi Xu,et al.  Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription , 2009, Proceedings of the National Academy of Sciences.

[27]  W. Noble,et al.  Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. , 2009, Trends in molecular medicine.

[28]  M. Pallàs,et al.  Modulation of SIRT1 expression in different neurodegenerative models and human pathologies , 2008, Neuroscience.

[29]  G. Cole,et al.  The role of insulin and neurotrophic factor signaling in brain aging and Alzheimer’s Disease , 2007, Experimental Gerontology.

[30]  G. Schellenberg,et al.  Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype , 2006, Neurobiology of Aging.

[31]  N. Åberg,et al.  Aspects of Growth Hormone and Insulin-Like Growth Factor-I Related to Neuroprotection, Regeneration, and Functional Plasticity in the Adult Brain , 2006, TheScientificWorldJournal.

[32]  M. Pallàs,et al.  Hyperphosphorylation of microtubule-associated protein tau in senescence-accelerated mouse (SAM) , 2005, Mechanisms of Ageing and Development.

[33]  J. Trojanowski,et al.  Initiation and Synergistic Fibrillization of Tau and Alpha-Synuclein , 2003, Science.

[34]  I. Grundke‐Iqbal,et al.  Levels of nonphosphorylated and phosphorylated tau in cerebrospinal fluid of Alzheimer's disease patients : an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay. , 2002, The American journal of pathology.

[35]  C. Culmsee,et al.  AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation , 2001, Journal of Molecular Neuroscience.

[36]  J. Morley,et al.  β-Amyloid precursor polypeptide in SAMP8 mice affects learning and memory , 2000, Peptides.

[37]  T. Takeda.  Senescence-accelerated mouse (SAM): a biogerontological resource in aging research , 1999, Neurobiology of Aging.

[38]  J. Ha,et al.  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. , 2015, Journal of Alzheimer's disease : JAD.

[39]  Benyi Li,et al.  Down-regulation of amyloid-β through AMPK activation by inhibitors of GSK-3β in SH-SY5Y and SH-SY5Y-AβPP695 cells. , 2012, Journal of Alzheimer's disease : JAD.

[40]  S. Monte.  Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimer's Disease , 2012 .

[41]  J. Koh,et al.  phosphorylation via AMPK and GSK3 , 2012 .

[42]  N. Tumosa,et al.  Beta-amyloid precursor polypeptide in SAMP8 mice affects learning and memory. , 2000, Peptides.