Kelly Dineley

Summary

Affiliation: University of Texas Medical Branch at Galveston
Location: Galveston, USA
URL: www.utmb.edu/neuro/faculty/KellyDineley.htm
Summary:
Insulin resistance increases the risk for developing AD yet it remains elusive as to how dysregulation of insulin signaling contributes to cognitive dysfunction in AD. Insulin sensitizers improve insulin responsiveness in people with diabetes and have thus been tested in several clinical trials for efficacy in AD. Recent trials on patients with MCI indicate that insulin sensitizers as well as intranasal insulin provide significant cognitive benefit suggesting that the insulin signaling axis can enhance cognitive function in AD. Insulin and insulin sensitizers impinge upon the insulin signaling pathway to target the expression of a plethora of genes including those classified as insulin-responsive genes. Activation of the isnuling signaling axis can facilitate memory consolidation by inducing expression of genes controlled by cyclic-AMP response elements (CREs) that are prototypically regulated by CREB and CBP transcription factors. Upstream from these memory consolidation gene transcription events is the common intermediate of insulin signaling, ERK MAPK (ERK), a signaling integrator required for learning and memory
We previously reported that the peroxisome-proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone (RSG) improved hippocampus-dependent cognition in the AD mouse model, Tg2576. RSG had no effect on wildtype littermate cognitive performance. Since ERK MAPK is required for many forms of learning and memory that are affected in AD, and since both PPARγ and ERK MAPK are key mediators of insulin signaling, we recently tested the hypothesis that RSG-mediated cognitive improvement induces a hippocampal PPARγ pattern of gene and protein expression that converges with the ERK MAPK signaling axis in Tg2576 AD mice that recapitulates mild cognitive impairment due to AD. In the hippocampal PPARγ transcriptome, we found significant overlap between PPRE-containing PPARγ target genes and ERK-regulated, CRE-containing target genes. Within the Tg2576 dentate gyrus proteome, RSG induced proteins with structural, energy, biosynthesis and plasticity functions. Several of these proteins are known to be important for cognitive function and are also regulated by ERK MAPK. In addition, we found the RSG-mediated augmentation of PPARγ and ERK2 activity during Tg2576 cognitive enhancement was reversed when hippocampal PPARγ was pharmacologically antagonized, revealing a coordinate relationship between PPARγ transcriptional competency and pERK that is reciprocally affected in response to chronic activation, compared to acute inhibition, of PPARγ. We conclude that the hippocampal transcriptome and proteome induced by cognitive enhancement with RSG harnesses a dysregulated ERK MAPK signal transduction pathway to overcome AD-like cognitive deficits in Tg2576 mice. Thus, PPARγ represents a signaling system that is not crucial for normal cognition yet can intercede to restore neural networks compromised by AD.
Grants:
ACTIVE
RO1AG031859 - NIH 07/01/2009

Publications

  1. ncbi request reprint α7 nicotinic acetylcholine receptors in Alzheimer's disease: neuroprotective, neurotrophic or both?
    Caterina M Hernandez
    Department of Neurology, University of Texas Medical Branch, 301 University Boulevard Route 0616, Galveston, Texas 77555 0616, USA
    Curr Drug Targets 13:613-22. 2012
  2. ncbi request reprint Beta-amyloid peptide--nicotinic acetylcholine receptor interaction: the two faces of health and disease
    Kelly T Dineley
    Department of Neurology, George and Cynthia Mitchell Research Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX 77555 0874, USA
    Front Biosci 12:5030-8. 2007
  3. ncbi request reprint Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression
    Adam R Cole
    Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee, Scotland, UK
    J Neurochem 103:1132-44. 2007
  4. pmc Selective induction of calcineurin activity and signaling by oligomeric amyloid beta
    Lindsay C Reese
    Department of Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, Texas, USA
    Aging Cell 7:824-35. 2008
  5. pmc Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition
    Giulio Taglialatela
    Department of Neurosciences and Cell Biology, The University of Texas Medical Branch at Galveston, TX 77555, USA
    Behav Brain Res 200:95-9. 2009
  6. pmc Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease
    Caterina M Hernandez
    Department of Neurology, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas 77555, USA
    J Neurosci 30:2442-53. 2010
  7. pmc Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice
    Kelly T Dineley
    Department of Neurology, University of Texas Medical Branch, Galveston, Texas 77555 1043, USA
    J Neurosci Res 88:2923-32. 2010
  8. pmc Rosiglitazone reversal of Tg2576 cognitive deficits is independent of peripheral gluco-regulatory status
    JENNIFER RODRIGUEZ-RIVERA
    Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555, United States
    Behav Brain Res 216:255-61. 2011
  9. doi request reprint Research update: Alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer's disease
    H Rheinallt Parri
    School of Life and Health Sciences, Aston University, Birmingham, UK
    Biochem Pharmacol 82:931-42. 2011
  10. pmc α-Synuclein oligomers oppose long-term potentiation and impair memory through a calcineurin-dependent mechanism: relevance to human synucleopathic diseases
    Zane S Martin
    Departments of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA
    J Neurochem 120:440-52. 2012

Research Grants

Collaborators

Detail Information

Publications25

  1. ncbi request reprint α7 nicotinic acetylcholine receptors in Alzheimer's disease: neuroprotective, neurotrophic or both?
    Caterina M Hernandez
    Department of Neurology, University of Texas Medical Branch, 301 University Boulevard Route 0616, Galveston, Texas 77555 0616, USA
    Curr Drug Targets 13:613-22. 2012
    ....
  2. ncbi request reprint Beta-amyloid peptide--nicotinic acetylcholine receptor interaction: the two faces of health and disease
    Kelly T Dineley
    Department of Neurology, George and Cynthia Mitchell Research Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX 77555 0874, USA
    Front Biosci 12:5030-8. 2007
    ..This review will discuss the extant literature on the subject in terms of clarifying this apparent dichotomy regarding the consequences of Abeta-nAChR interaction during health and disease...
  3. ncbi request reprint Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression
    Adam R Cole
    Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee, Scotland, UK
    J Neurochem 103:1132-44. 2007
    ..These observations implicate hyperphosphorylation of CRMP2 as an early event in the development of AD and suggest that it can be induced by a severe APP over-expression and/or processing defect...
  4. pmc Selective induction of calcineurin activity and signaling by oligomeric amyloid beta
    Lindsay C Reese
    Department of Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, Texas, USA
    Aging Cell 7:824-35. 2008
    ....
  5. pmc Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition
    Giulio Taglialatela
    Department of Neurosciences and Cell Biology, The University of Texas Medical Branch at Galveston, TX 77555, USA
    Behav Brain Res 200:95-9. 2009
    ..In human AD, CaN inhibition may lead the way for therapeutics to improve declarative memory performance as demonstrated in a mouse model for AD...
  6. pmc Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease
    Caterina M Hernandez
    Department of Neurology, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas 77555, USA
    J Neurosci 30:2442-53. 2010
    ....
  7. pmc Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice
    Kelly T Dineley
    Department of Neurology, University of Texas Medical Branch, Galveston, Texas 77555 1043, USA
    J Neurosci Res 88:2923-32. 2010
    ..Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric A beta treatment in mice...
  8. pmc Rosiglitazone reversal of Tg2576 cognitive deficits is independent of peripheral gluco-regulatory status
    JENNIFER RODRIGUEZ-RIVERA
    Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555, United States
    Behav Brain Res 216:255-61. 2011
    ....
  9. doi request reprint Research update: Alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer's disease
    H Rheinallt Parri
    School of Life and Health Sciences, Aston University, Birmingham, UK
    Biochem Pharmacol 82:931-42. 2011
    ....
  10. pmc α-Synuclein oligomers oppose long-term potentiation and impair memory through a calcineurin-dependent mechanism: relevance to human synucleopathic diseases
    Zane S Martin
    Departments of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA
    J Neurochem 120:440-52. 2012
    ..These results indicate that exogenously applied αSyn oligomers impact neuronal function and produce memory deficits through mechanisms that involve CaN activation...
  11. pmc Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice
    Kelly T Dineley
    Department of Neurology, The University of Texas Medical Branch at Galveston, 301 University Blvd, Galveston, TX 77555 1043, USA
    Neurobiol Learn Mem 88:217-24. 2007
    ..These results indicate that calcineurin may mediate some of the cognitive effects of excess Abeta such that inhibition of calcineurin shall be further explored as a potential treatment to reverse cognitive impairments in AD...
  12. ncbi request reprint Phosphorylation of CREB and DARPP-32 during late LTP at hippocampal to prefrontal cortex synapses in vivo
    Maïté Hotte
    INSERM, U796, Pathophysiology of Psychiatric Disorders, University Paris Descartes, Faculty of Medecine Paris Descartes, 2ter rue d Alesia, Paris F 75014, France
    Synapse 61:24-8. 2007
    ..These findings support the hypothesis that prolonged expression of hippocampal-prefrontal cortex LTP depends on a synergistic mechanism involving phosphorylation of both CREB and DARPP-32 via activation of the cAMP/PKA-dependent pathway...
  13. ncbi request reprint Amino acid determinants of alpha 7 nicotinic acetylcholine receptor surface expression
    K T Dineley
    Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA
    J Biol Chem 275:13974-85. 2000
    ..How these surface expression determinants in the alpha7 nicotinic acetylcholine receptor might influence synaptic efficacy is discussed...
  14. ncbi request reprint Leitmotifs in the biochemistry of LTP induction: amplification, integration and coordination
    K T Dineley
    Division of Neuroscience, Baylor College of Medicine, Houston, Texas, USA
    J Neurochem 77:961-71. 2001
    ..Among these themes are signal amplification, signal integration and signal coordination. Here we use these themes as an organizing context for reviewing the profusion of signaling mechanisms involved in the induction of LTP...
  15. ncbi request reprint Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease
    K T Dineley
    Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA
    J Neurosci 21:4125-33. 2001
    ....
  16. ncbi request reprint Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins
    Kelly T Dineley
    Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA
    J Biol Chem 277:22768-80. 2002
    ..These findings provide two robust and rapid assays for beta-amyloid-associated effects that can be performed on young animals: impaired contextual fear learning and up-regulation of alpha 7 nicotinic receptors...
  17. pmc Cognitive enhancement with rosiglitazone links the hippocampal PPARγ and ERK MAPK signaling pathways
    Larry A Denner
    Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas 77555, USA
    J Neurosci 32:16725-35a. 2012
    ..Thus, PPARγ represents a signaling system that is not crucial for normal cognition yet can intercede to restore neural networks compromised by AD...
  18. ncbi request reprint beta -Amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes
    Kelly T Dineley
    Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA
    J Biol Chem 277:25056-61. 2002
    ..Thus, when beta-amyloid peptide activation of alpha7 receptors occurs, these currents are comprised, at least in part, of Ca(2+)...
  19. ncbi request reprint Postsynaptic contributions to hippocampal network hyperexcitability induced by chronic activity blockade in vivo
    Cynthia D Galvan
    The Cain Foundation Laboratories, Department of Pediatrics and Division of Neuroscience, Baylor College of Medicine, 6621 Fannim St, MC 3 6365, Houston, TX 77030, USA
    Eur J Neurosci 18:1861-72. 2003
    ..Postsynaptic changes are likely to be the major contributors to the hippocampal network hyperexcitability and should enhance both excitatory synaptic efficacy and plasticity...
  20. ncbi request reprint Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis
    R Wang
    Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, M320, Houston, TX 77030, USA
    Neuroscience 126:305-12. 2004
    ..However, short-term and long-term synaptic plasticity in both area CA1 and dentate gyrus are not affected. Our results suggest that impaired adult neurogenesis may contribute to the memory deficit associated with FAD...
  21. ncbi request reprint MAPK recruitment by beta-amyloid in organotypic hippocampal slice cultures depends on physical state and exposure time
    Karen A Bell
    Division of Neuroscience, Baylor College of Medicine, Houston, Texas, USA
    J Neurochem 91:349-61. 2004
    ..These data indicate the existence of differential coupling of alpha7 to downstream targets depending on the type of ligand that leads to receptor activation...
  22. ncbi request reprint D1 receptor modulation of memory retrieval performance is associated with changes in pCREB and pDARPP-32 in rat prefrontal cortex
    Maïté Hotte
    INSERM, U796, Pathophysiology of Psychiatric Disorders, University Paris Descartes, Faculty of Medecine Paris Descartes, France
    Behav Brain Res 171:127-33. 2006
    ..These results provide insight into molecular mechanisms involved in D(1) receptor-dependent modulation of short- versus long-term memory in prefrontal cortex where DARPP-32 in synergy with CREB may represent a pivotal role...
  23. ncbi request reprint Nicotinic acetylcholine receptor interaction with beta-amyloid: molecular, cellular, and physiological consequences
    R H Parri
    Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555 0616, USA
    Curr Alzheimer Res 7:27-39. 2010
    ....

Research Grants2

  1. Mechanisms of PPAR-gamma Enhancement of Cognitive Function in Alzheimer's Disease
    KELLY T contact DINELEY; Fiscal Year: 2010
    ..These findings will have significant impact on our understanding of, and treatment options for, Alzheimer's disease. ..