Alzheimer's disease (AD) is a devastating and irreversible neurological disease that progressively alters personality and behavior, and destroys cognitive function. With an annual price tag exceeding 100 billion dollars, AD is also one of the nation's most costly diseases. In recent years, anti-inflammatory agents have emerged as promising compounds for delaying the onset of AD symptoms. Yet, our understanding of the mechanisms underlying neuro-immune/inflammatory (im/inf) signaling in the brain remains incomplete. The Ca2+/calmodulin dependent protein phosphatase, calcineurin, plays a critical role in im/inf signaling cascades in lymphocytes and other cell types, but has received little consideration for a similar role in nervous tissue. In the past year, we found that calcineurin activation in neuron-glia co-cultures was sufficient for recapitulating several components of the im/inf response found consistently with aging and AD, including astrocyte activation and the induction of numerous im/inf-related gene cascades. We also observed a marked and selective upregulation of calcineurin in activated astrocytes surrounding amyloid deposits in AD model mice. The long-term goal of this project is to therefore test the hypothesis that calcineurin is a critical component for the activation of im/inf signaling processes associated with AD. The first two aims will test whether activation of calcineurin and/or the calcineurin-dependent transcription factor, NFAT is necessary for im/inf signaling in astrocytes. Biologically relevant inflammatory mediators will be delivered to astrocyte- specific cultures in the presence or absence of potent calcineurin and NFAT inhibitors. The induction of im/inf markers will be assessed with Western blots, RT-PCR, and cytokine arrays. Potential Ca2+ sources for calcineurin activation in astrocytes will also be examined, along with the possibility that calcineurin amplifies its own activity by up-regulating these Ca2+ sources.
Aim three will use cell fractionation, immunoprecipitation, Western blot, phosphatase activity assays, immunohistochemistry, and in situ hybridization to qualitatively and quantitatively assess changes in calcineurin signaling in AD brain specimens and/or in a rodent model of AD. Completion of these studies will greatly increase our knowledge of the role of calcineurin in neuroinflammation and AD, and may lead to the development of novel treatment strategies for this disease and other degenerative conditions where neuroinflammation is prominent. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG027297-01A1
Application #
7145081
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Wise, Bradley C
Project Start
2006-09-01
Project End
2011-06-30
Budget Start
2006-09-01
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$270,293
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Norris, Christopher M (2018) Calcineurin: directing the damage in Alzheimer disease: An Editorial for 'Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain' on page 24. J Neurochem 147:8-11
Kraner, Susan D; Norris, Christopher M (2018) Astrocyte Activation and the Calcineurin/NFAT Pathway in Cerebrovascular Disease. Front Aging Neurosci 10:287
Castonguay, David; Dufort-Gervais, Julien; Ménard, Caroline et al. (2018) The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline. Curr Biol 28:1079-1089.e4
Price, Brittani R; Norris, Christopher M; Sompol, Pradoldej et al. (2018) An emerging role of astrocytes in vascular contributions to cognitive impairment and dementia. J Neurochem 144:644-650
Sompol, Pradoldej; Norris, Christopher M (2018) Ca2+, Astrocyte Activation and Calcineurin/NFAT Signaling in Age-Related Neurodegenerative Diseases. Front Aging Neurosci 10:199
Sompol, Pradoldej; Furman, Jennifer L; Pleiss, Melanie M et al. (2017) Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in A?-Bearing Mice. J Neurosci 37:6132-6148
Pettigrew, L Creed; Kryscio, Richard J; Norris, Christopher M (2016) The TNF?-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, and Post-Ischemic Cell Loss. PLoS One 11:e0154721
Norris, Christopher M; Sompol, Pradoldej; Roberts, Kelly N et al. (2016) Pycnogenol protects CA3-CA1 synaptic function in a rat model of traumatic brain injury. Exp Neurol 276:5-12
Lovell, Mark A; Lynn, Bert C; Fister, Shuling et al. (2016) A Novel Small Molecule Modulator of Amyloid Pathology. J Alzheimers Dis 53:273-87
Furman, Jennifer L; Sompol, Pradoldej; Kraner, Susan D et al. (2016) Blockade of Astrocytic Calcineurin/NFAT Signaling Helps to Normalize Hippocampal Synaptic Function and Plasticity in a Rat Model of Traumatic Brain Injury. J Neurosci 36:1502-15

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