Alzheimer's disease (AD) is the most common type of the debilitating dementias. It is initially characterized by impaired acquisition of new memories inevitably leading to an unrelenting decline in cognitive function. Recent analyses of human postmortem AD brains identified major impairments in insulin signaling while epidemiological studies have showed that type 2 diabetes is a risk factor for AD. Further, AD patients themselves exhibit type 2-like insulin resistance leading to the ongoing clinical trials testing the type 2 diabetes therapeutic RTZ in AD patient. RTZ (RTZ, trade name: Avandia) is a member of the thiazolidinedione (TZD) family of insulin-sensitizing drugs that are potent pharmacological ligands for peroxisome proliferator-activated receptor gamma (PPARg). Tg2576 transgenic mice express a mutant human form of APP that causes AD in humans, making this mouse line one of the most extensively studied animal models for AD. As such, these animals mimic several aspects of AD patients, most notably age-dependent AB accumulation, cognitive deficits that are first apparent in hippocampus-selective learning and memory tasks, and insulin dysregulation. In this proposal we hypothesize that CNS PPARg is an important mediator of cognitive function in AD. Our preliminary studies show that the PPARg agonist, RTZ, reversed hippocampus-dependent memory impairment in Tg2576 mice, increased hippocampal PPARg DNA binding activity, decreased phosphorylation-dependent inhibition of PPARg, ameliorated APP-dependent dysregulation of the insulin signaling axis and PPARg itself, and reversed hyperinsulinemia. These observations support the hypothesis that CNS PPARg activity is important for cognitive function under conditions of excess AB due to overexpression of mutant human APP. Currently, little is known about the regulation of CNS PPARg or the molecular mechanisms mediating RTZ-induced PAPRg activity in the CNS. To test our hypothesis, this project will define the PPARg signaling axis that rescues contextual fear conditioning deficits in the Tg2576 mouse model of AD (Aim 1), determine the role of PPARg in cognitive functions mediated both within and outside the hippocampus (Aim 2), determine the neuronal readouts for cognitive rescue in Tg2576 brain resulting from PPARg agonism (Aim 3). Ultimately, these studies will describe the role of PPARg in cognitive dysfunction in AD, connect the behavioral and molecular mechanisms of AD, and have significant impact on our understanding of, and treatment options for, AD.

Public Health Relevance

Alzheimer's disease is characterized by an inexorable decline in cognitive function. In an animal model of Alzheimer's disease, this proposal will determine the molecular mechanisms of a therapeutic modality, rosiglitazone, currently in clinical trials and will evaluate its broad applicability to diverse cognitive deficits. These findings will have significant impact on our understanding of, and treatment options for, Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Refolo, Lorenzo
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University of Texas Medical Br Galveston
Schools of Medicine
United States
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Hsu, Wei-Chun J; Wildburger, Norelle C; Haidacher, Sigmund J et al. (2017) PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease. Exp Neurol 295:1-17
Velazquez, Ramon; Tran, An; Ishimwe, Egide et al. (2017) Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease. Neurobiol Aging 58:1-13
Nenov, Miroslav N; Tempia, Filippo; Denner, Larry et al. (2015) Impaired firing properties of dentate granule neurons in an Alzheimer's disease animal model are rescued by PPAR? agonism. J Neurophysiol 113:1712-26
Nenov, Miroslav N; Laezza, Fernanda; Haidacher, Sigmund J et al. (2014) Cognitive enhancing treatment with a PPAR? agonist normalizes dentate granule cell presynaptic function in Tg2576 APP mice. J Neurosci 34:1028-36
Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry (2014) Insulin resistance in Alzheimer's disease. Neurobiol Dis 72 Pt A:92-103
Jahrling, Jordan B; Hernandez, Caterina M; Denner, Larry et al. (2014) PPAR? recruitment to active ERK during memory consolidation is required for Alzheimer's disease-related cognitive enhancement. J Neurosci 34:4054-63
Denner, Larry A; Rodriguez-Rivera, Jennifer; Haidacher, Sigmund J et al. (2012) Cognitive enhancement with rosiglitazone links the hippocampal PPARýý and ERK MAPK signaling pathways. J Neurosci 32:16725-35a
Rodriguez-Rivera, Jennifer; Denner, Larry; Dineley, Kelly T (2011) Rosiglitazone reversal of Tg2576 cognitive deficits is independent of peripheral gluco-regulatory status. Behav Brain Res 216:255-61