Klotho and Neurodegenerative Disease

Klotho 和神经退行性疾病

• 批准号: 9234077
• 负责人: Dena Bou Dubal
• 金额: $ 35.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234077
• 关键词: Acute; Aging; Alleles; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Biological Markers; Brain; Brain Diseases; Cleaved cell; Clinical; Cognition; Cognitive; Cognitive Therapy; Cognitive deficits; Communication; Data; Development; Disease; Functional disorder; Genetic Variation; Hormonal; Hormones; Human; Impaired cognition; Impairment; Individual; Investigation; Lead; Learning; Life; Light; Longevity; Measures; Mediating; Medical; Membrane; Memory; Molecular; Molecular Probes; Molecular Target; Motor; Mus; NMDA receptor A1; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Onset of illness; Parkinson Disease; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Population; Proteins; Reporting; Signal Transduction; Structure; Synapses; Testing; Therapeutic; Toxic effect; Transgenic Organisms; alpha synuclein; arm; cognitive enhancement; cognitive function; genetic variant; human disease; motor disorder; mouse model; mouse synuclein alpha; neuroimaging; normal aging; novel strategies; novel therapeutics; overexpression; prevent; proteomic signature; public health relevance; relating to nervous system; resilience; synaptic function

 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.

 描述（由申请人提供）：由于神经退行性疾病引起的认知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疗法的问题。Klotho是一种促进长寿的激素，在从其膜形式分裂后在整个身体和大脑中循环。我们最近发现，klotho在整个生命周期中广泛的、遗传驱动的增加增强了正常小鼠的认知能力，部分原因是通过突触富集关键的学习和记忆分子。与小鼠平行，我们发现由于遗传变异，具有较高水平的全身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升高增强了小鼠的认知能力，这些小鼠同时模拟了阿尔茨海默病（AD）和帕金森病（PD）。这些发现很重要，因为认知缺陷是这两种疾病的主要表现，甚至有助于PD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Aβ和α-突触核蛋白毒性靶点上的机制-例如在突触上。突触是AD和PD的病理生理学的靶点，被klotho富集，并且是神经通信和功能的中心。因此，了解klotho诱导的突触结构和分子变化将成为剖析其弹性机制的一个汇聚点。我们假设klotho通过突触富集机制赋予认知弹性以对抗与神经退行性疾病相关的缺陷。我们将追求三个目标。 1)在目标1中，我们将描述klotho对Aβ和α-突触核蛋白的弹性的影响2）在目标2中，我们将探索突触中协调弹性的分子靶点3）在目标3中，我们将描述人类疾病中的关键关联。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如何在突触处赋予这种针对Aβ和α-突触核蛋白的会聚靶点的作用。它们还可以直接导致开发迫切需要的认知功能障碍治疗方法，以“提高AD和PD等神经退行性疾病的恢复力”。