# Hippocampal Synaptic Structure

> **NIH NIH R37** · UNIVERSITY OF KENTUCKY · 2020 · $512,543

## Abstract

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.

## Key facts

- **NIH application ID:** 9905377
- **Project number:** 5R37AG004542-31
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** PHILIP W. LANDFIELD
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $512,543
- **Award type:** 5
- **Project period:** 1998-01-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905377

## Citation

> US National Institutes of Health, RePORTER application 9905377, Hippocampal Synaptic Structure (5R37AG004542-31). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9905377. Licensed CC0.

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