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.

Public Health Relevance

Metabolic syndrome and diabetes are age- and obesity-related diseases that are rapidly approaching epidemic proportions in our society. Recent studies indicate that there may be a link between metabolic syndrome and cognitive decline. The underlying mechanisms through which individual components of peripheral metabolic dysregulation can negatively impact brain function are not known. Our research will identify new links between brain aging, diabetes and obesity. If successful, our project could impact public health by providing strong clues to help identify novel therapeutic targets and prevent cognitive decline in aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Neurobiology of Learning and Memory Study Section (LAM)
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Petanceska, Suzana
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University of Kentucky
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Frazier, Hilaree N; Maimaiti, Shaniya; Anderson, Katie L et al. (2017) Calcium's role as nuanced modulator of cellular physiology in the brain. Biochem Biophys Res Commun 483:981-987
Berkowitz, Bruce A; Lenning, Jacob; Khetarpal, Nikita et al. (2017) In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. FASEB J 31:4179-4186
Maimaiti, Shaniya; Frazier, Hilaree N; Anderson, Katie L et al. (2017) Novel calcium-related targets of insulin in hippocampal neurons. Neuroscience 364:130-142
Anderson, Katie L; Frazier, Hilaree N; Maimaiti, Shaniya et al. (2017) Impact of Single or Repeated Dose Intranasal Zinc-free Insulin in Young and Aged F344 Rats on Cognition, Signaling, and Brain Metabolism. J Gerontol A Biol Sci Med Sci 72:189-197
Maimaiti, Shaniya; Anderson, Katie L; DeMoll, Chris et al. (2016) Intranasal Insulin Improves Age-Related Cognitive Deficits and Reverses Electrophysiological Correlates of Brain Aging. J Gerontol A Biol Sci Med Sci 71:30-9
Maimaiti, Shaniya; DeMoll, Chris; Anderson, Katie L et al. (2015) Short-lived diabetes in the young-adult ZDF rat does not exacerbate neuronal Ca(2+) biomarkers of aging. Brain Res 1621:214-21
Latimer, Caitlin S; Brewer, Lawrence D; Searcy, James L et al. (2014) Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats. Proc Natl Acad Sci U S A 111:E4359-66
Thibault, Olivier; Anderson, Katie L; DeMoll, Chris et al. (2013) Hippocampal calcium dysregulation at the nexus of diabetes and brain aging. Eur J Pharmacol 719:34-43
Pancani, Tristano; Anderson, Katie L; Brewer, Lawrence D et al. (2013) Effect of high-fat diet on metabolic indices, cognition, and neuronal physiology in aging F344 rats. Neurobiol Aging 34:1977-87
Searcy, James L; Phelps, Jeremiah T; Pancani, Tristano et al. (2012) Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer's disease. J Alzheimers Dis 30:943-61

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