Neurobiology and Therapeutic Potential of Klotho

描述（由申请人提供）：认知功能（如学习和记忆）具有基本的生物学重要性，影响这些功能的疾病是我们这个时代最具挑战性的生物医学问题。我们最近获得的证据表明，多效蛋白klotho的水平升高可增强小鼠和人类的认知功能，并可预防模拟阿尔茨海默病（AD）关键方面的转基因小鼠模型中的突触和认知障碍。Klotho是I类跨膜蛋白，其胞外域通过蛋白水解切割释放。在外周，它主要由肾脏产生。在中枢神经系统（CNS）中，它主要由脉络丛产生，在特定的神经元群体中观察到较低的表达水平，特别是在海马中。虽然各种证据表明klotho可以延缓衰老和衰老相关疾病，但它在CNS中的功能以及它在神经系统疾病中可能发挥的作用在很大程度上是未知的。在我们的初步研究中，增加转基因小鼠全身klotho的产量不仅增强了中年和老年小鼠的学习和记忆，而且也增强了年轻小鼠的学习和记忆。此外，KLOTHO变体（KL-VS）的杂合子人类携带者血清中klotho水平升高，并且在一系列认知测试中表现优于非携带者。同样，这种klotho效应在很大的年龄范围内都可以看到。全球klotho升高还可以预防人淀粉样前体蛋白（hAPP）转基因小鼠中AD相关的突触、神经网络和认知功能障碍。我们假设klotho通过一种独立于衰老的机制改善了正常和患病大脑的神经功能。我们还假设，增加klotho或其影响可以抵消升高的淀粉样蛋白的致病作用？（A？）在大脑中的水平，并可能有助于预防AD。为了验证这些假设，并帮助揭示这种迷人的蛋白质在大脑中的功能，我们提出了三个具体目标。目的1将探索增加klotho的外周产生是否会改善突触和认知功能，或者是否必须在血脑屏障内升高klotho水平才能实现这些有益效果。它将 还确定了从脉络丛上皮细胞释放到脑脊液中的分泌型klotho相对于在特定神经元群体中表达的全长klotho的相对重要性。目的2将检查klotho在不同生命阶段的CNS中表达的功能重要性，并确定klotho从大脑中消耗的潜在致病影响，这与衰老有关，在AD患者中很突出。目标3将探索增加klotho水平增强突触和认知功能的潜在机制，特别强调谷氨酸受体和相关信号通路。拟议的研究将填补重要的知识空白，并可以为独立项目中klotho相关疗法的开发提供关键指导。

DESCRIPTION (provided by applicant): Cognitive functions such as learning and memory are of fundamental biological importance and diseases that affect these functions are among the most challenging biomedical problems of our time. We recently obtained evidence indicating that elevating levels of the pleotropic protein klotho enhances cognitive functions in mice and humans and can prevent synaptic and cognitive impairments in a transgenic mouse model simulating key aspects of Alzheimer's disease (AD). Klotho is a class I transmembrane protein whose ectodomain is released by proteolytic cleavage. In the periphery, it is produced predominantly by the kidney. Within the central nervous system (CNS), it is produced predominantly by the choroid plexus, with lower levels of expression seen in specific neuronal populations, particularly in the hippocampus. While diverse lines of evidence suggest that klotho delays aging and aging-related diseases, the functions it fulfills in the CNS and the roles it migh play in neurological disease are largely unknown. In our preliminary studies, increasing klotho production throughout the body of transgenic mice enhanced learning and memory not only in middle-aged and old mice, but also in young mice. Moreover, heterozygous human carriers of a KLOTHO variant (KL-VS) had elevated levels of klotho in the serum and performed better in a battery of cognitive tests than non-carriers. Again, this klotho effect was seen across a wide age range. Global klotho elevation also prevented AD-related synaptic, neural network and cognitive dysfunctions in human amyloid precursor protein (hAPP) transgenic mice. We hypothesize that klotho improves neural functions in both normal and diseased brains through a mechanism that is independent of aging. We also hypothesize that augmenting klotho or its effects can counteract the pathogenic effects of elevated amyloid-? (A?) levels in the brain and may help prevent AD. To test these hypotheses and help unravel the functions of this fascinating protein in the brain, we propose three specific aims. Aim 1 will explore whether increasing the peripheral production of klotho improves synaptic and cognitive functions or whether klotho levels must be elevated within the blood-brain barrier to achieve these beneficial effects. It will also ascertain the relative importance of secreted klotho released from choroid plexus epithelial cells into the cerebrospinal fluid versus full-length klotho expressed in specific neuronal populations. Aim 2 will examine the functional importance of klotho expression in the CNS at different life stages and define the potential pathogenic impact of klotho depletion from the brain, which occurs with aging and is prominent in humans with AD. Aim 3 will explore potential mechanisms by which increased klotho levels enhance synaptic and cognitive functions, with a particular emphasis on glutamate receptors and related signaling pathways. The proposed studies will fill important knowledge gaps and could provide critical guidance for the development of klotho-related therapeutics in independent projects.