KLOTHO and Resilience to Synaptic Dysfunction in Preclinical AD

KLOTHO 和临床前 AD 中突触功能障碍的恢复力

• 批准号: 10587987
• 负责人: OZIOMA C OKONKWO
• 金额: $ 77.75万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587987
• 关键词: Abate; Address; Adult; Adverse effects; Age; Age-associated memory impairment; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid beta-42; Amyloid beta-Protein; Attenuated; Belief; Biological Markers; Blood; Brain; Caregivers; Central Nervous System; Cerebrospinal Fluid; Clinical; Cognitive; Cognitive deficits; Dementia; Dependence; Deterioration; Disease; Elderly; Exhibits; Functional disorder; Genes; Genetic Risk; Genotype; Health; Healthcare Systems; Heterozygote; Human; Imaging ligands; Impaired cognition; Incidence; Individual; Integral Membrane Protein; Investigation; Kinetics; Light; Longevity; Mediating; Memory; Memory Loss; Metabolism; Methodology; Modification; N-Methylaspartate; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Onset of illness; Participant; Pathologic; Patients; Phenotype; Play; Positioning Attribute; Positron-Emission Tomography; Process; Public Health; Registries; Research; Research Priority; Resistance; Resources; Risk; Risk Factors; Senile Plaques; Societies; Synapses; Synaptic plasticity; Syndrome; Tsunami; Variant; Wisconsin; Work; abeta accumulation; age effect; age related; aging gene; alpha synuclein; anti aging; apolipoprotein E-4; attenuation; beta amyloid pathology; blood-based biomarker; clinically relevant; cognitive performance; cohort; curative treatments; density; disability; druggable target; executive function; follow-up; heuristics; human old age (65+); in vivo; indexing; individual variation; insight; longevity gene; middle age; mouse model; multimodality; nervous system disorder; neurofilament; neurogranin; neuropathology; neurotoxic; pre-clinical; prevent; resilience; sex; socioeconomics; stem; symptom management; synaptic function; tau Proteins; tau-1; translational study; uptake; β-amyloid burden

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD), a progressive and debilitating neurological disorder of old age, is clinically hallmarked by memory loss and neuropathologically by accumulation of Aβ plaques and neurofibrillary tangles in the brain. Synaptic dysfunction has recently emerged as another early key feature of AD; evidence suggests that synaptic density decreases up to 30% in preclinical stages of AD and correlates more closely with cognitive deficits than Aβ pathology. Although age is the single biggest risk factor for developing AD, the observation that even individuals at genetic risk for AD or harboring AD neuropathology are able to remain cognitively normal as they age has refocused research away from risk and underscored the need for investigations of the factors that confer resilience in hopes of reducing disability and disease incidence. KLOTHO is dubbed an anti-aging and longevity gene, and plays a key role in cellular metabolism, central nervous system maturation, and synaptic plasticity. Critical to this proposal is that KLOTHO also seems to enhance synaptic integrity and protects from neurodegeneration. Thus, this integrative, clinically relevant project will rigorously investigate whether KLOTHO 1) confers resilience against age- and AD-related synaptic dysfunction, and 2) modifies the relationship between such dysfunction and cognitive decline both cross-sectionally and longitudinally. The proposed study will be embedded within the robust framework of two well-characterized and longitudinally followed cohorts of ~2,000 at-risk, late-middle-aged adults (the Wisconsin Registry for Alzheimer’s Prevention [WRAP] and the Wisconsin Alzheimer’s Disease Research Center [WADRC]). All participants are already genotyped for KLOTHO and have been cognitively phenotyped for up to 20 years under WRAP/WADRC. The R01 will provide resources for a subset of these participants (N=150) to undergo multimodal biomarker assessment ([11C]UCB-J PET imaging, CSF and blood-based biomarkers) at baseline and 2-year follow-up. Completion of this study has the potential to provide invaluable insights and druggable targets for forestalling brain/cognitive deterioration with advancing age or AD pathological burden.

项目摘要/摘要 阿尔茨海默氏病（AD）是一种渐进的和令人衰弱的老年神经系统疾病，是 临床上的记忆力丧失和神经病理学在临床上通过Aβ斑块的积累和 大脑中的神经原纤维缠结。突触功能障碍最近出现了 广告的主要特征；有证据表明，临床前的突触密度最多降低30％ 与Aβ病理学相比，AD的阶段与认知缺陷更紧密相关。虽然年龄 是开发AD的最大危险因素，这一观察结果是，即使是遗传的人 随着年龄的增长 将研究重新集中于风险，并强调需要调查这些因素 赋予弹性，希望减少残疾和疾病事件。克洛托被称为 抗衰老和寿命基因，并且在细胞代谢中起关键作用，中枢神经系统 成熟和突触可塑性。该提议至关重要的是，克洛托似乎也 增强突触完整性并保护神经变性。这是临床上的整合性 相关项目将严格研究Klotho 1）承认对年龄的韧性 - 和与广告相关的突触功能障碍，以及2）修改这种功能障碍之间的关系 在横截面和纵向上的认知能力下降。拟议的研究将是 嵌入两个特征和纵向的稳健框架中 约有2,000名高风险，中间年龄的成年人（威斯康星州阿尔茨海默氏症登记册 预防[Wrap]和威斯康星州阿尔茨海默氏病研究中心[WADRC]）。全部 参与者已经对Klotho进行了基因分型，并且已被认知表型 在包裹/wadrc下20年。 R01将为这些参与者的子集提供资源 （n = 150）进行多模式生物标志物评估（[11C] UCB-J PET成像，CSF和 基线和2年随访时，基于血液的生物标志物。这项研究的完成 有可能提供宝贵的见解和可吸毒目标，以防止大脑/认知 随着年龄或AD病理负担的发展而恶化。