Hippocampal Synaptic Structure

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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.