FK506-Binding Protein 12.6/1b (FKBP1b) stabilizes intracellular calcium release in heart cells but its role in brain neurons has been unknown. During the preceding phase of this project, we conducted systematic tests of our working hypothesis that an aging-related decline in FKBP1b underlies many calcium-mediated aspects of unhealthy brain aging. These studies showed that reproducing the proposed pathogenic decline with FKBP1b knockdown in the hippocampus recapitulated the calcium dysregulation brain aging syndrome in young rats. Conversely, counteracting the aging-related hippocampal FKBP1b decline by using virally- mediated FKBP1b overexpression fully reversed calcium dysregulation and cognitive impairment in aged rats (Gant et al, 2011; 2014; 2015), thereby providing strong support for this novel hypothesis on the molecular basis of unhealthy brain aging. Subsequent long term studies using behavioral and gene expression assessment revealed that cognitive rescue was similarly effective after 7 months and after 2 months of FKBP1b overexpression. Further, cognitive aging changes and rescue by FKBP1b correlated with age related changes in calpain gene and protein expression and with cytoskeletal gene expression (Gant et al, in prep.). Based on these findings, we propose the following specific aims for the next phase of research:
Aim 1. Corticosterone and vitamin D are steroid hormones that regulate calcium related biomarkers of hippocampal aging in opposite directions. Therefore, we will test the hypothesis that these two naturally occurring hormonal factors act on brain aging processes by modulating FKBP1b.
Aim 2. Based on findings in the preceding phase, we will test the hypothesis that downstream negative effects of declining FKBP1b are mediated in part by the calpain pathway.
Aim 3. We will use rodent models to test aspects of the intriguing hypothesis that aging related changes in hippocampal and entorhinal FKBP1b expression link normal brain aging to increased risk of Alzheimer's disease.

Public Health Relevance

The increasing aging population in the U.S. (20% of the population will be >65 years of age by the year 2030) often has cognitive decline, that can significantly affect quality of life and profoundly add to health care burden. Our results indicate that a specific pathway (FKBP-Ca2+) plays a critical role in brain aging and cognitive decline; thus the goal of this project is to use gene therapy techniques to determine whether such interventions can prevent or slow the onset of age-related brain decline. The outcomes may have substantial

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Wise, Bradley C
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University of Kentucky
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Gant, John C; Blalock, Eric M; Chen, Kuey-Chu et al. (2018) FK506-Binding Protein 12.6/1b, a Negative Regulator of [Ca2+], Rescues Memory and Restores Genomic Regulation in the Hippocampus of Aging Rats. J Neurosci 38:1030-1041
Gant, John C; Kadish, Inga; Chen, Kuey-Chu et al. (2018) Aging-Related Calcium Dysregulation in Rat Entorhinal Neurons Homologous with the Human Entorhinal Neurons in which Alzheimer's Disease Neurofibrillary Tangles First Appear. J Alzheimers Dis 66:1371-1378
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
Alzheimer's Association Calcium Hypothesis Workgroup (2017) Calcium Hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimers Dement 13:178-182.e17
Gant, John C; Chen, Kuey-Chu; Kadish, Inga et al. (2015) Reversal of Aging-Related Neuronal Ca2+ Dysregulation and Cognitive Impairment by Delivery of a Transgene Encoding FK506-Binding Protein 12.6/1b to the Hippocampus. J Neurosci 35:10878-87
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
Gant, J C; Blalock, E M; Chen, K-C et al. (2014) FK506-binding protein 1b/12.6: a key to aging-related hippocampal Ca2+ dysregulation? Eur J Pharmacol 739:74-82
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
Thibault, Olivier; Pancani, Tristano; Landfield, Philip W et al. (2012) Reduction in neuronal L-type calcium channel activity in a double knock-in mouse model of Alzheimer's disease. Biochim Biophys Acta 1822:546-9

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