Klotho and Neurodegenerative Disease

描述（由申请人提供）：由于神经退行性疾病引起的认知能力下降正在成为我们最大的生物医学挑战之一-我们没有有效的医学治疗方法的问题。Klotho是一种促进长寿的激素，在其膜形态分裂后在整个身体和大脑中循环。我们最近发现，在正常小鼠的一生中，基因驱动的klotho的广泛增加增强了认知能力，部分原因是关键学习和记忆分子的突触富集。与小鼠相比，我们发现，由于基因变异，具有较高水平系统性klotho的个体表现出比平均水平更好的认知功能。然后，我们在小鼠模型中测试了klotho的有益作用是否延伸到神经退行性疾病相关的缺陷和病理。事实上，转基因klotho基因的升高提高了阿尔茨海默病（AD）和帕金森病（PD）模型小鼠的认知能力。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PD患者的运动功能障碍。我们的新数据表明，klotho在患病的大脑中赋予认知弹性，可能是通过聚集在a β和α-突触核蛋白毒性靶点上的机制，例如突触。突触是阿尔茨海默病和帕金森病的病理生理目标，由klotho富集，是神经通讯和功能的中心。因此，了解klotho诱导的突触结构和分子变化将是解剖其弹性机制的一个交汇点。我们假设klotho通过突触富集机制赋予与神经退行性疾病相关的认知恢复力。我们将追求三个目标。1)在Aim 1中，我们将描述klotho对Aβ和α-突触核蛋白的恢复力的影响；2)在Aim 2中，我们将探索协调恢复力的突触中的分子靶点；3)在Aim 3中，我们将分析人类疾病的关键关联。这些研究可以从根本上推进我们对认知弹性的理解，以及klotho如何在突触中对Aβ和α-突触核蛋白的趋同目标产生这种作用。它们还可以直接导致认知功能障碍急需的治疗方法的发展，这些治疗方法可以“增强AD和PD等神经退行性疾病的恢复能力”。

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.