Klotho and Neurodegenerative Disease

描述(由申请人提供)：由于神经退行性疾病导致的认知能力下降正在成为我们最大的生物医学挑战之一--这个问题我们没有有效的医学治疗方法。Klotho是一种促进长寿的荷尔蒙，它从膜上分解后在全身和大脑中循环。我们最近发现，随着寿命的延长，广泛的、由基因驱动的klotho增加增强了正常小鼠的认知能力，部分是通过突触丰富关键的学习和记忆分子。与老鼠平行，我们发现由于遗传变异而导致全身klotho水平较高的个体，其认知功能表现优于平均水平。然后，我们测试了Klotho的有益效果是否延伸到小鼠模型中与神经退行性疾病相关的缺陷和病理。事实上，转基因Klotho Elevation增强了对阿尔茨海默氏症(AD)和帕金森氏病(PD)模型小鼠的认知。这些发现很重要，因为认知缺陷是这两种疾病的关键表现，甚至会导致帕金森病患者的运动功能障碍。我们的新数据表明，Klotho赋予患病大脑认知韧性，可能是通过聚集Aβ和α-突触核蛋白毒性目标的机制--例如在突触。突触是阿尔茨海默病和帕金森病病理生理学的靶点，富含Klotho，是神经交流和功能的中心。因此，了解Klotho诱导的突触的结构和分子变化将是剖析其弹性机制的一个聚合点。我们假设，klotho通过突触丰富的机制，对与神经退行性疾病相关的缺陷赋予了认知弹性。我们将追求三个目标。1)在目标1中，我们将表征Klotho对Aβ和α-突触核蛋白的弹性的影响。2)在目标2中，我们将探索协调弹性的突触的分子靶点。3)在目标3中，我们将概述人类疾病中的关键关联。这些研究可以从根本上促进我们对认知弹性的理解，以及Klotho如何针对突触上Aβ和α-突触核蛋白的聚合靶标赋予这种效应。它们还可以直接导致认知功能障碍急需的治疗方法的开发，这些方法可以在AD和PD等神经退行性疾病中增强韧性。

DESCRIPTION (provided by applicant): Cognitive decline due to neurodegenerative disease is emerging as one of our greatest biomedical challenges - a problem for which we have no effective medical therapies. Klotho is a longevity-promoting hormone that circulates throughout the body and brain following cleavage from its membrane form. We recently found that widespread, genetically-driven increases in klotho over the lifespan enhanced cognition in normal mice, in part through synaptic enrichment of key learning and memory molecules. In parallel with mice, we found that individuals with higher levels of systemic klotho, due to a genetic variant, showed better than average cognitive functions. We then tested whether the beneficial effect of klotho extends to neurodegenerative disease-related deficits and pathologies in mouse models. Indeed, transgenic klotho elevation enhanced cognition in mice that model aspects of both Alzheimer's (AD) and Parkinson's disease (PD). These findings are important since cognitive deficits are a key manifestation of both diseases, and even contribute to motor dysfunctions in PD. Our new data suggest that klotho confers cognitive resilience in a diseased brain, possibly through mechanisms that converge upon targets of Aβ and α-synuclein toxicity - such as at the synapse. Synapses are targeted by the pathophysiology of AD and PD, enriched by klotho, and central to neural communication and function. Thus, understanding klotho-induced structural and molecular changes to the synapse will be a convergent point in dissecting its mechanisms of resilience. We hypothesize that klotho confers cognitive resilience against deficits related to neurodegenerative disease through mechanisms of synaptic enrichment. We will pursue three aims. 1) In Aim 1, we will characterize effects of klotho on resilience to Aβ and α-synuclein 2) In Aim 2 we will explore molecular targets at the synapse that orchestrate resilience 3) In Aim 3, we will profile key associations in human disease. These studies could fundamentally advance our understanding of cognitive resilience and how klotho confers this effect against converging targets of Aβ and α-synuclein at the synapse. They could also, directly, lead to the development of urgently needed treatments for cognitive dysfunction that "boost resilience" in neurodegenerative conditions like AD and PD.