Hippocampal Synaptic Structure

FK506结合蛋白12.6/1b(FKBP1b)稳定心肌细胞内钙释放 大脑神经元一直不为人知。在这个项目的前一阶段，我们进行了系统的测试 我们的工作假设是，FKBP1b的衰老相关下降是许多钙调节的基础 不健康的大脑老化的各个方面。这些研究表明，复制所提出的致病衰退 随着FKBP1b在海马区的敲除，重现了钙调节失调的脑衰老综合征 在幼鼠身上。相反，通过病毒使用来对抗与衰老相关的海马区FKBP1b的下降- FKBP1b过表达可完全逆转老年大鼠钙调节障碍和认知功能障碍 老鼠(Gant等人，2011；2014；2015)，从而为这一关于 不健康脑老化的分子基础。随后使用行为和基因进行的长期研究 表情评估显示，认知救援在7个月后和2个月后同样有效 数月FKBP1b过度表达。此外，认知老化变化和FKBP1b的挽救与 钙蛋白基因和蛋白表达与细胞骨架基因表达的增龄相关变化(Gant et Al，在准备中。)。 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： 目的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。 海马区向相反方向老化。因此，我们将检验这两个自然存在的假设 正在发生的荷尔蒙因素通过调节FKBP1b作用于大脑衰老过程。 目标2.基于前一阶段的发现，我们将检验下游负面影响的假设 FKBP1b减少的影响部分是通过钙蛋白酶途径来调节的。 目的3.我们将使用啮齿动物模型来测试这一耐人寻味的假设的各个方面，即与衰老相关的变化 在海马区和内嗅区，FKBP1b的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.