Brain Aging Effects of Klotho

 描述(申请人提供)：蛋白质表达随年龄的变化从根本上改变大脑微环境。特定蛋白表达的变化如何影响大脑衰老和疾病的发展仍然知之甚少。Klotho最初被描述为长寿蛋白，在大脑中被下调年龄，并根据其蛋白表达水平促进认知障碍或增强。我们的初步数据显示，Klotho在出生后的神经发生和海马区的突触可塑性中都发挥了作用。海马体功能是认知功能的关键，对老年的影响特别敏感。Klotho介导的对海马体功能的影响可能是在基因敲除和过度表达的动物中测量的认知效应的基础。这项拟议研究的长期目标是了解klotho的年龄下调对认知的功能影响，从而了解klotho如何影响海马体的功能。利用Klotho蛋白表达水平差异的小鼠和病毒载体模型，将质疑Klotho蛋白表达对于随着年龄的增长而持续的海马体功能所需的中心假设。这一假说建立在初步数据的基础上，这些数据揭示了神经干细胞发育和突触可塑性的差异，并伴随着Klotho蛋白表达的增加或减少。为了验证这一假说，将进行三个具体目标：1)测试脑源性klotho表达通过抑制神经营养信号来调节海马区功能的假说；2)确定脑源性klotho表达的长期丧失是否导致海马区退化；3)测试klotho表达增强是否足以防止认知衰老。在具体目标1中，我们将利用我们的新小鼠模型来确定大脑中的klotho是否调节认知结果。目的2将确定在全球klotho基因敲除中快速发作的认知损害和应激标志物是否是神经退化的前驱。目标3将测试是否可以在中年提高klotho，以支持健康的大脑老化。这项工作对于确定klotho在正常麸皮功能中的作用具有重要意义，并为klotho对认知的影响是否通过其在神经发生或突触可塑性中的作用提供了新的信息。该应用程序在使用肛门模型方面具有创新性，允许对klotho表达水平进行有针对性的操作。通过了解klotho在大脑中的功能，我们将对正常大脑老化和病理性疾病发展的机制有更深入的了解。

 DESCRIPTION (provided by applicant): Changes in protein expression with age fundamentally alter the brain micro-environment. How changes in expression of specific proteins impact brain aging and development of disease remains poorly understood. Klotho, originally described as longevity protein, is age-downregulated in brain and promotes cognitive impairment or enhancement dependent on its level of protein expression. Our preliminary data show a role for klotho in both postnatal neurogenesis and synaptic plasticity of the hippocampus. Hippocampal function is critical in cognitive function and is particularly sensitive to the effects of advanced age. Klotho mediated effects on hippocampal function could underlie cognitive effects measured in knockout and overexpressing animals. The long-term goal of the proposed research is to understand the functional consequences on cognition caused by age-downregulation of klotho and thus how klotho affects hippocampal function over lifespan. Using mouse and viral vector models of klotho protein expression level differences, the central hypothesis that klotho expression is required for sustained hippocampal function with age will be interrogated. The hypothesis is based on preliminary data revealing differences in the neural stem cell development and synaptic plasticity concomitant with increased or decreased expression of klotho protein. To investigate the hypothesis three specific aims will be conducted: 1) Test the hypothesis that brain-derived klotho expression regulates hippocampal function by inhibition of neurotrophic signaling; 2) Determine whether long-term loss of brain- derived klotho causes hippocampal degeneration; 3) Test whether enhanced klotho expression is sufficient to prevent cognitive aging. In specific aim 1, we will utilize our novel mouse models to determine whether klotho in the brain mediates cognitive outcomes. Aim 2 will determine whether the rapid onset of cognitive impairment and markers of stress in the global klotho knockout are the precursors to neurodegeneration. Aim 3 will test whether klotho can be elevated in mid-life to support healthy brain aging. The work is significant in identifying a role for klotho in normal bran function and provides new information as to whether klotho's effects on cognition are mediated by its role in neurogenesis or synaptic plasticity. The application is innovative in its use of anial models to allow targeted manipulation of klotho expression level. By understanding how klotho functions in the brain, we will obtain greater insight into mechanisms underlying both normal brain aging and pathological disease development.