Age-related metabolic and neurodegenerative changes in SAMP8 mice

The most important risk factor for the development of sporadic Alzheimer’s disease (AD) is ageing. Senescence accelerated mouse prone 8 (SAMP8) is a model of sporadic AD, with senescence accelerated resistant mouse (SAMR1) as a control. In this study, we aimed to determine the onset of senescence-induced neurodegeneration and the related potential therapeutic window using behavioral experiments, immunohistochemistry and western blotting in SAMP8 and SAMR1 mice at 3, 6 and 9 months of age. The Y-maze revealed significantly impaired working spatial memory of SAMP8 mice from the 6th month. With ageing, increasing plasma concentrations of proinflammatory cytokines in SAMP8 mice were detected as well as significantly increased astrocytosis in the cortex and microgliosis in the brainstem. Moreover, from the 3rd month, SAMP8 mice displayed a decreased number of neurons and neurogenesis in the hippocampus. From the 6th month, increased pathological phosphorylation of tau protein at Thr231 and Ser214 was observed in the hippocampi of SAMP8 mice. In conclusion, changes specific for neurodegenerative processes were observed between the 3rd and 6th month of age in SAMP8 mice; thus, potential neuroprotective interventions could be applied between these ages.

[1]  A. Ramírez,et al.  Nicotinamide as potential biomarker for Alzheimer’s disease: A translational study based on metabolomics , 2021, Frontiers in Molecular Biosciences.

[2]  B. Železná,et al.  Palmitoylated prolactin-releasing peptide reduced Aβ plaques and microgliosis in the cerebellum: APP/PS1 mice study. , 2021, Current Alzheimer Research.

[3]  B. Železná,et al.  Aging and high-fat diet feeding lead to peripheral insulin resistance and sex-dependent changes in brain of mouse model of tau pathology THY-Tau22 , 2021, Journal of Neuroinflammation.

[4]  Meng Li,et al.  A UPLC-Q-TOF/MS-Based Metabolomics Study on the Effect of Corallodiscus flabellatus (Craib) B. L. Burtt Extract on Alzheimer's Disease , 2021, Evidence-based complementary and alternative medicine : eCAM.

[5]  Y. Shirai,et al.  Motor Dyscoordination and Alteration of Functional Correlation Between DGKγ and PKCγ in Senescence-Accelerated Mouse Prone 8 (SAMP8) , 2021, Frontiers in Aging Neuroscience.

[6]  J. Kopecký,et al.  GPR10 gene deletion in mice increases basal neuronal activity, disturbs insulin sensitivity and alters lipid homeostasis. , 2021, Gene.

[7]  H. Izu,et al.  Low-Dose Ethanol Has Impacts on Plasma Levels of Metabolites Relating to Chronic Disease Risk in SAMP8 mice. , 2020, Journal of nutritional science and vitaminology.

[8]  Jie Liu,et al.  SAMP8 Mice as a Model of Age-Related Cognition Decline with Underlying Mechanisms in Alzheimer's Disease. , 2020, Journal of Alzheimer's disease : JAD.

[9]  L. Kořínková,et al.  Inflammation: major denominator of obesity, Type 2 diabetes and Alzheimer's disease-like pathology? , 2020, Clinical science.

[10]  R. Sengoku.  Aging and Alzheimer's disease pathology , 2019, Neuropathology : official journal of the Japanese Society of Neuropathology.

[11]  F. Lenfant,et al.  Sex differences in metabolic regulation and diabetes susceptibility , 2019, Diabetologia.

[12]  Xiaoxu Zhang,et al.  Volatile organic compounds fingerprinting in faeces and urine of Alzheimer's disease model SAMP8 mice by headspace-gas chromatography-ion mobility spectrometry and headspace-solid phase microextraction-gas chromatography-mass spectrometry. , 2019, Journal of chromatography. A.

[13]  G. Brewer,et al.  Age- and AD-related redox state of NADH in subcellular compartments by fluorescence lifetime imaging microscopy , 2019, GeroScience.

[14]  P. Fraser,et al.  The Link Between Tau and Insulin Signaling: Implications for Alzheimer’s Disease and Other Tauopathies , 2019, Front. Cell. Neurosci..

[15]  C. Hölscher,et al.  Liraglutide and a lipidized analog of prolactin-releasing peptide show neuroprotective effects in a mouse model of β-amyloid pathology , 2019, Neuropharmacology.

[16]  B. Spiegelman,et al.  New Advances in Adaptive Thermogenesis: UCP1 and Beyond. , 2019, Cell metabolism.

[17]  P. Guest,et al.  The Y-Maze for Assessment of Spatial Working and Reference Memory in Mice. , 2018, Methods in molecular biology.

[18]  Chunfu Wu,et al.  Pseudoginsenoside‐F11 alleviates cognitive deficits and Alzheimer's disease‐type pathologies in SAMP8 mice , 2019, Pharmacological research.

[19]  Nicholas M. Vogt,et al.  The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease , 2018, Alzheimer's Research & Therapy.

[20]  David S. Wishart,et al.  MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis , 2018, Nucleic Acids Res..

[21]  P. Maher,et al.  Fisetin Reduces the Impact of Aging on Behavior and Physiology in the Rapidly Aging SAMP8 Mouse , 2018, The journals of gerontology. Series A, Biological sciences and medical sciences.

[22]  M. Fakhoury.  Microglia and Astrocytes in Alzheimer's Disease: Implications for Therapy , 2017, Current neuropharmacology.

[23]  Jiangang Liu,et al.  Fuzheng Quxie Decoction Ameliorates Learning and Memory Impairment in SAMP8 Mice by Decreasing Tau Hyperphosphorylation , 2017, Evidence-based complementary and alternative medicine : eCAM.

[24]  Hung‐wen Liu,et al.  An alternative model for studying age-associated metabolic complications: Senescence-accelerated mouse prone 8 , 2017, Experimental Gerontology.

[25]  Sterling C. Johnson,et al.  Gut microbiome alterations in Alzheimer’s disease , 2017, Scientific Reports.

[26]  H. Budka,et al.  SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda's legacy and future directions , 2017, Neuropathology : official journal of the Japanese Society of Neuropathology.

[27]  W. Banks,et al.  The SAMP8 mouse for investigating memory and the role of insulin in the brain , 2017, Experimental Gerontology.

[28]  S. Cuzzocrea,et al.  Indoxyl Sulfate Affects Glial Function Increasing Oxidative Stress and Neuroinflammation in Chronic Kidney Disease: Interaction between Astrocytes and Microglia , 2017, Front. Pharmacol..

[29]  C. Fontes-Ribeiro,et al.  Impact of Neuroinflammation on Hippocampal Neurogenesis: Relevance to Aging and Alzheimer's Disease. , 2017, Journal of Alzheimer's disease : JAD.

[30]  J. Güell-Bosch,et al.  Mouse Models of Alzheimer's Disease. , 2017, Journal of Alzheimer's disease : JAD.

[31]  Zhuojing Luo,et al.  CaMKII-Mediated CREB Phosphorylation Is Involved in Ca2+-Induced BDNF mRNA Transcription and Neurite Outgrowth Promoted by Electrical Stimulation , 2016, PloS one.

[32]  M. Haluzík,et al.  Urinary metabolomic profiling in mice with diet-induced obesity and type 2 diabetes mellitus after treatment with metformin, vildagliptin and their combination , 2016, Molecular and Cellular Endocrinology.

[33]  S. Endo,et al.  Early onset of behavioral alterations in senescence-accelerated mouse prone 8 (SAMP8) , 2016, Behavioural Brain Research.

[34]  S. Monte.  Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer’s Disease , 2016, Drugs.

[35]  D. Novák,et al.  Strategy for NMR metabolomic analysis of urine in mouse models of obesity--from sample collection to interpretation of acquired data. , 2015, Journal of pharmaceutical and biomedical analysis.

[36]  J. Jelsing,et al.  The GLP-1 Receptor Agonist Liraglutide Improves Memory Function and Increases Hippocampal CA1 Neuronal Numbers in a Senescence-Accelerated Mouse Model of Alzheimer’s Disease , 2015, Journal of Alzheimer's disease : JAD.

[37]  F. Wang,et al.  Long-term acarbose administration alleviating the impairment of spatial learning and memory in the SAMP8 mice was associated with alleviated reduction of insulin system and acetylated H4K8 , 2015, Brain Research.

[38]  D. Novák,et al.  Metabolomic profiling of urinary changes in mice with monosodium glutamate-induced obesity , 2015, Analytical and Bioanalytical Chemistry.

[39]  S. Ferreira,et al.  Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer's disease , 2014, Alzheimer's & Dementia.

[40]  Jing Zhang,et al.  Tripchlorolide improves age-associated cognitive deficits by reversing hippocampal synaptic plasticity impairment and NMDA receptor dysfunction in SAMP8 mice , 2014, Behavioural Brain Research.

[41]  R. Colbran,et al.  CaMKII: a molecular substrate for synaptic plasticity and memory. , 2014, Progress in molecular biology and translational science.

[42]  Holger Jahn,et al.  Memory loss in Alzheimer's disease , 2013, Dialogues in clinical neuroscience.

[43]  M. O’Banion,et al.  Chronic neuron- and age-selective down-regulation of TNF receptor expression in triple-transgenic Alzheimer disease mice leads to significant modulation of amyloid- and Tau-related pathologies. , 2013, The American journal of pathology.

[44]  S. Welle,et al.  Muscle mTORC1 suppression by IL-6 during cancer cachexia: a role for AMPK. , 2013, American journal of physiology. Endocrinology and metabolism.

[45]  T. Tashiro,et al.  Alterations in local thyroid hormone signaling in the hippocampus of the SAMP8 mouse at younger ages: Association with delayed myelination and behavioral abnormalities , 2013, Journal of neuroscience research.

[46]  N. Bhat,et al.  Increased tau phosphorylation and impaired brain insulin/IGF signaling in mice fed a high fat/high cholesterol diet. , 2013, Journal of Alzheimer's disease : JAD.

[47]  Jianchun Yu,et al.  Hippocampal neuron loss is correlated with cognitive deficits in SAMP8 mice , 2013, Neurological Sciences.

[48]  S. Kida.  A Functional Role for CREB as a Positive Regulator of Memory Formation and LTP , 2012, Experimental neurobiology.

[49]  G. Brewer,et al.  A Reversible Early Oxidized Redox State That Precedes Macromolecular ROS Damage in Aging Nontransgenic and 3xTg-AD Mouse Neurons , 2012, The Journal of Neuroscience.

[50]  E. Vara,et al.  Melatonin can improve insulin resistance and aging-induced pancreas alterations in senescence-accelerated prone male mice (SAMP8) , 2012, AGE.

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

[52]  J. del Valle,et al.  Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer's disease. , 2012, Journal of Alzheimer's disease : JAD.

[53]  Ying Liu,et al.  Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes , 2011, The Journal of pathology.

[54]  B. Hyman,et al.  Neuropathological alterations in Alzheimer disease. , 2011, Cold Spring Harbor perspectives in medicine.

[55]  Baoxin Li,et al.  Limited hippocampal neurogenesis in SAMP8 mouse model of Alzheimer's disease , 2011, Brain Research.

[56]  Declan G. M. Murphy,et al.  Hippocampal Proton MR Spectroscopy in Early Alzheimer’s Disease and Mild Cognitive Impairment , 2011, Brain Topography.

[57]  Q. Garrett,et al.  Role of carnitine in disease , 2010, Nutrition & metabolism.

[58]  R. DeFronzo,et al.  Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes , 2009, Diabetes Care.

[59]  B. Gualano,et al.  Exploring the therapeutic role of creatine supplementation , 2009, Amino Acids.

[60]  Liegang Liu,et al.  Ameliorative effects of lotus seedpod proanthocyanidins on cognitive deficits and oxidative damage in senescence-accelerated mice , 2008, Behavioural Brain Research.

[61]  H. Tanila,et al.  Tau hyperphosphorylation correlates with reduced methylation of protein phosphatase 2A , 2008, Neurobiology of Disease.

[62]  Xian-Zhong Yan,et al.  NMR-based metabonomic investigations into the metabolic profile of the senescence-accelerated mouse. , 2008, Journal of proteome research.

[63]  S. Kersten,et al.  Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation. , 2007, Endocrinology.

[64]  R. Cox,et al.  A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human. , 2007, Physiological genomics.

[65]  M. Armoni,et al.  Transcriptional regulation of the GLUT4 gene: from PPAR-γ and FOXO1 to FFA and inflammation , 2007, Trends in Endocrinology & Metabolism.

[66]  M. Armoni,et al.  Transcriptional regulation of the GLUT4 gene: from PPAR-gamma and FOXO1 to FFA and inflammation. , 2007, Trends in endocrinology and metabolism: TEM.

[67]  H. Senn,et al.  Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in 1H NMR metabonomics. , 2006, Analytical chemistry.

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

[69]  Hiroyuki Aburatani,et al.  Skeletal Muscle FOXO1 (FKHR) Transgenic Mice Have Less Skeletal Muscle Mass, Down-regulated Type I (Slow Twitch/Red Muscle) Fiber Genes, and Impaired Glycemic Control*[boxs] , 2004, Journal of Biological Chemistry.

[70]  D. Alkon,et al.  Insulin and the insulin receptor in experimental models of learning and memory. , 2004, European journal of pharmacology.

[71]  M. Miyamoto,et al.  Involvement of the glutamatergic system in behavioral disorders in senescence-accelerated mice (SAMP8) , 2004 .

[72]  J. Kushner,et al.  Insulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation , 2003, The Journal of Neuroscience.

[73]  Stephanie Ringeissen,et al.  Potential urinary and plasma biomarkers of peroxisome proliferation in the rat: identification of N-methylnicotinamide and N-methyl-4-pyridone-3-carboxamide by 1H nuclear magnetic resonance and high performance liquid chromatography , 2003, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[74]  E. Brunamonti,et al.  Evaluation of the elevated plus-maze and open-field tests for the assessment of anxiety-related behaviour in inbred mice , 2002, Behavioural Brain Research.

[75]  J. Bohl,et al.  Stage-dependent and sector-specific neuronal loss in hippocampus during Alzheimer's disease , 2002, Acta Neuropathologica.

[76]  C. Franceschi,et al.  Inflamm‐aging: An Evolutionary Perspective on Immunosenescence , 2000 .

[77]  G J Brewer,et al.  Protective Effect of the Energy Precursor Creatine Against Toxicity of Glutamate and β‐Amyloid in Rat Hippocampal Neurons , 2000, Journal of neurochemistry.

[78]  T. Bártfai,et al.  IL-6 is essential in TNF-alpha-induced fever. , 1998, The American journal of physiology.

[79]  T. Bártfai,et al.  IL-6 is essential in TNF-α-induced fever. , 1998, American journal of physiology. Regulatory, integrative and comparative physiology.

[80]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[81]  K. Tracey,et al.  Spermine Inhibits Proinflammatory Cytokine Synthesis in Human Mononuclear Cells: A Counterregulatory Mechanism that Restrains the Immune Response , 1997, The Journal of experimental medicine.

[82]  M. Hosokawa,et al.  Senescence-accelerated mouse (SAM): A novel murine model of senescence , 1997, Experimental Gerontology.

[83]  N. Rothwell,et al.  Febrile response to tissue inflammation involves both peripheral and brain IL-1 and TNF-alpha in the rat. , 1997, The American journal of physiology.

[84]  I. Akiguchi,et al.  Spontaneous Spongy Degeneration of the Brain Stem in SAM-P/8 Mice, a Newly Developed Memory-Deficient Strain , 1989, Journal of neuropathology and experimental neurology.

[85]  J. Blusztajn,et al.  Formation of methylamines from ingested choline and lecithin. , 1983, The Journal of pharmacology and experimental therapeutics.

[86]  Keiichi Higuchi,et al.  A new murine model of accelerated senescence , 1981, Mechanisms of Ageing and Development.