Hippocampal Synaptic Structure

FK 506结合蛋白12.6/1b（FKBP 1b）稳定心脏细胞内钙释放，但其在心肌细胞凋亡中的作用 脑神经元是未知的。在本项目的前一阶段，我们进行了系统的测试 我们的工作假设是，FKBP 1b的衰老相关下降是许多钙介导的 不健康的大脑老化的方面。这些研究表明，复制所提出的致病性下降， FKBP 1b在海马中的敲低再现了钙调节失调的脑老化综合征 在年轻的老鼠。相反，通过使用病毒- 介导的FKBP 1b过表达完全逆转了老年人的钙失调和认知障碍 大鼠（Gant et al，2011; 2014; 2015），从而为这一新假设提供了有力的支持。 不健康的大脑衰老的分子基础。随后的长期研究使用行为和基因 表达评估显示，认知拯救在7个月后和2个月后同样有效。 FKBP 1b过度表达的时间。此外，认知老化的变化和FKBP 1b的拯救与以下因素相关： 钙蛋白酶基因和蛋白表达以及细胞骨架基因表达的年龄相关变化（Gant et al，in prep.）。 基于这些发现，我们为下一阶段的研究提出了以下具体目标： 目标1.皮质酮和维生素D是类固醇激素，调节钙相关的生物标志物， 海马体的衰老方向相反因此，我们将测试这两个自然的假设， 发生的激素因子通过调节FKBP 1b作用于脑老化过程。 目标2.基于前一阶段的发现，我们将检验下游阴性 FKBP 1b下降的作用部分由钙蛋白酶途径介导。 目标3。我们将使用啮齿类动物模型来测试这个有趣的假设的各个方面，即衰老相关的变化 海马和内嗅FKBP 1b表达将正常脑老化与阿尔茨海默病风险增加联系起来 疾病

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.