Metabolic syndrome and hippocampal Ca2+ dysregulation in aging memory decline

Summary

Principal Investigator: Olivier Thibault
Abstract: DESCRIPTION (provided by applicant): Increasing epidemiological and experimental evidence shows that factors associated with metabolic syndrome, including glucose dysregulation, insulin insensitivity, and/or obesity, are linked to cognitive decline in aging. Moreover, the incidence of obesity and metabolic syndrome are approaching epidemic proportions. The thiazolidinediones (TZD), selective peroxisome proliferator-activated receptor-gamma (PPAR3) agonists, improve several aspects of metabolic syndrome including lowering insulin resistance, glucose and cholesterol levels in Type 2 diabetics, and have also been linked to decreased inflammation and 2-amyloid load in models of Alzheimer's disease (AD). However, the mechanisms that link peripheral metabolic syndrome to brain dysfunction are still poorly understood, and few studies have analyzed these periphery-brain relationships in aged animals. Over the past years, we and others have found considerable electrophysiological and imaging evidence that hippocampal Ca2+ dysregulation with aging correlates with cognitive decline. Recently, our gene microarray studies also revealed downregulation of hippocampal insulin and glucose signaling that correlated with aging-related memory impairment. Here, we will test the working hypothesis that peripheral components of metabolic syndrome induce alterations in Ca2+ homeostasis in the hippocampus by acting on L-type voltage-gated Ca2+ channels (L-VGCCs), NMDARs, Ca2+-induced Ca2+ release (CICR), and the Ca2+-dependent afterhyperpolarization (AHP), thereby negatively affecting synaptic plasticity (LTP) and cognitive function. We will also test the hypothesis that these actions are mediated in part by changes in brain insulin/glucose signaling pathways and can be counteracted by TZDs. Specific Aim # 1 will study F344 male rats fed a normal diet and determine, at 7-8 and 18-20 months of age, which component of metabolic dysregulation most closely associates with measures of cognitive function, and hippocampal electrophysiological/imaging function (L-VGCCs, NMDARs, CICR, AHPs, and LTP). Specific Aim #2 will test whether diet-induced obesity (DIO) exacerbates neurobiological, cognitive, gene expression and neuropathological indices of brain aging and whether interventions with TZDs can slow or reverse this process. Specific Aim #3 will analyze the effects of insulin on hippocampal slices, testing for direct effects on electrophysiological markers of aging, and will test the sub-hypothesis that neurons from aged animals exhibit insulin resistance. Together, these multidisciplinary studies will provide one of the first systematic analyses of links between variables contributing to peripheral metabolic syndrome and cellular mechanisms of brain aging. Therefore, even if the central hypothesis is rejected, the studies proposed will provide more definitive evidence for the impact o metabolic syndrome, as well as the actions of TZDs, on the brain.
Funding Period: 2009-08-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc Action potential throughput in aged rat hippocampal neurons: regulation by selective forms of hyperpolarization
    John C Gant
    Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center UKMC, MS320, Lexington, KY 40503, United States
    Neurobiol Aging 30:2053-64. 2009
  2. pmc Aging-related gene expression in hippocampus proper compared with dentate gyrus is selectively associated with metabolic syndrome variables in rhesus monkeys
    Eric M Blalock
    Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky 40536, USA
    J Neurosci 30:6058-71. 2010
  3. pmc Effects of long-term pioglitazone treatment on peripheral and central markers of aging
    Eric M Blalock
    Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, Kentucky, United States of America
    PLoS ONE 5:e10405. 2010
  4. pmc Imaging of a glucose analog, calcium and NADH in neurons and astrocytes: dynamic responses to depolarization and sensitivity to pioglitazone
    Tristano Pancani
    Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, United States
    Cell Calcium 50:548-58. 2011
  5. pmc Reduction in neuronal L-type calcium channel activity in a double knock-in mouse model of Alzheimer's disease
    Olivier Thibault
    Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY 40536, USA
    Biochim Biophys Acta 1822:546-9. 2012
  6. pmc Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer's disease
    James L Searcy
    Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, KY 40536 0084, USA
    J Alzheimers Dis 30:943-61. 2012
  7. pmc Effect of high-fat diet on metabolic indices, cognition, and neuronal physiology in aging F344 rats
    Tristano Pancani
    Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, KY 40536 0084, USA
    Neurobiol Aging 34:1977-87. 2013
  8. pmc Hippocampal calcium dysregulation at the nexus of diabetes and brain aging
    Olivier Thibault
    Department of Molecular and Biomedical Pharmacology, MS 313, 800 Rose Street, University of Kentucky Medical Center, Lexington, KY 40536, United States Electronic address
    Eur J Pharmacol 719:34-43. 2013

Research Grants

  1. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  2. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  3. Novel Mechanisms of NSAID Action in Alzheimer's Disease
    Edward H Koo; Fiscal Year: 2013
  4. Impact of Amyloid on the Aging Brain
    Reisa A Sperling; Fiscal Year: 2013
  5. Egg to Embryo: Gene Regulatory Circuitry in Development
    Eric H Davidson; Fiscal Year: 2013
  6. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
  7. EARLY INDICATORS OF LATER WORK LEVELS, DISEASE AND DEATH
    Dora L Costa; Fiscal Year: 2013
  8. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
  9. Alerations of Sleep and Circadian Timing in Aging
    Eve Van Cauter; Fiscal Year: 2013
  10. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013

Detail Information

Publications8

  1. pmc Action potential throughput in aged rat hippocampal neurons: regulation by selective forms of hyperpolarization
    John C Gant
    Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center UKMC, MS320, Lexington, KY 40503, United States
    Neurobiol Aging 30:2053-64. 2009
    ..Together, these results are consistent with a model in which the source of the hyperpolarization is important in determining hippocampal spike throughput within the theta frequency range...
  2. pmc Aging-related gene expression in hippocampus proper compared with dentate gyrus is selectively associated with metabolic syndrome variables in rhesus monkeys
    Eric M Blalock
    Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky 40536, USA
    J Neurosci 30:6058-71. 2010
    ..In turn, these MSI-associated neuroenergetic changes may promote inflammation, neuronal vulnerability, and risk of cognitive impairment/AD...
  3. pmc Effects of long-term pioglitazone treatment on peripheral and central markers of aging
    Eric M Blalock
    Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, Kentucky, United States of America
    PLoS ONE 5:e10405. 2010
    ..Because aging is a common risk factor for both AD and T2DM, we investigated whether the TZD, pioglitazone could alter brain aging under non-pathological conditions...
  4. pmc Imaging of a glucose analog, calcium and NADH in neurons and astrocytes: dynamic responses to depolarization and sensitivity to pioglitazone
    Tristano Pancani
    Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, United States
    Cell Calcium 50:548-58. 2011
    ....
  5. pmc Reduction in neuronal L-type calcium channel activity in a double knock-in mouse model of Alzheimer's disease
    Olivier Thibault
    Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY 40536, USA
    Biochim Biophys Acta 1822:546-9. 2012
    ..The results suggest that mechanisms for Ca(2+) dysregulation can differ substantially between animal models of normal aging and models of pathological aging...
  6. pmc Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer's disease
    James L Searcy
    Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, KY 40536 0084, USA
    J Alzheimers Dis 30:943-61. 2012
    ..Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain...
  7. pmc Effect of high-fat diet on metabolic indices, cognition, and neuronal physiology in aging F344 rats
    Tristano Pancani
    Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, KY 40536 0084, USA
    Neurobiol Aging 34:1977-87. 2013
    ..Interestingly, although peripheral glucose regulation was relatively insensitive to HFD, the brain appeared to show greater sensitivity to HFD in F344 rats...
  8. pmc Hippocampal calcium dysregulation at the nexus of diabetes and brain aging
    Olivier Thibault
    Department of Molecular and Biomedical Pharmacology, MS 313, 800 Rose Street, University of Kentucky Medical Center, Lexington, KY 40536, United States Electronic address
    Eur J Pharmacol 719:34-43. 2013
    ..Thus, while additional testing is needed, the results to date are consistent with the view that strategies that enhance insulin signaling can counteract the effect of aging on Ca(2+) dysregulation. ..

Research Grants30

  1. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  2. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  3. Novel Mechanisms of NSAID Action in Alzheimer's Disease
    Edward H Koo; Fiscal Year: 2013
    ..By providing additional preclinical and clinical information on GAMs, such studies should contribute significantly to the further development of GSMs as Alzheimer's therapeutics. ..
  4. Impact of Amyloid on the Aging Brain
    Reisa A Sperling; Fiscal Year: 2013
    ..This PPG brings together an exceptional multidisciplinary team of clinical, statistical, cognitive neuroscience, imaging, and laboratory investigators dedicated to exploring the impact of amyloid on the aging brain. ..
  5. Egg to Embryo: Gene Regulatory Circuitry in Development
    Eric H Davidson; Fiscal Year: 2013
    ..In the DAVIDSON COMPONENT the GRN will be expanded to include all regulatory genes predicted by genomic analysis, and observed to be expressed specifically in the endomesodermal territories, (cont.) ..
  6. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  7. EARLY INDICATORS OF LATER WORK LEVELS, DISEASE AND DEATH
    Dora L Costa; Fiscal Year: 2013
    ..Project 4 deals with the differences across urban and rural areas in the process of aging. ..
  8. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  9. Alerations of Sleep and Circadian Timing in Aging
    Eve Van Cauter; Fiscal Year: 2013
    ..Core B (Methods and Analysis) will standard operating procedures for data collection, archival and analysis. Core C will assay peripheral levels of hormones, cytokines and other blood constituents. ..
  10. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  11. The Aging Pituitary-Gonadal Axis
    George R Bousfield; Fiscal Year: 2013
    ..While currently available preparations work well in young women, they become increasingly ineffective in older women, requiring higher doses and prolonged administration yet producing fewer oocytes. ..
  12. Mayo Alzheimer's Disease Research Center
    Ronald C Petersen; Fiscal Year: 2013
    ..The ADRC will also continue to be a training platform for young investigators. ..
  13. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  14. Neural Correlates and Modifiers of Cognitive Aging
    Naftali Raz; Fiscal Year: 2013
    ..abstract_text> ..
  15. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..