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.

项目概要/摘要 阿尔茨海默病 (AD) 是一种进行性、使人衰弱的老年神经系统疾病， 临床上以记忆丧失为特征，神经病理学上以 Aβ 斑块的积累为特征 大脑中的神经原纤维缠结最近成为另一种早期现象。 AD 的关键特征；证据表明临床前突触密度降低高达 30% AD 的各个阶段与认知缺陷的相关性比 Aβ 病理学的相关性更密切。 是罹患 AD 的最大风险因素，据观察，即使是具有遗传基因的个体 患有 AD 的风险或患有 AD 神经病理学的人能够随着年龄的增长而保持认知正常 重新将研究重点从风险转移出来，并强调需要调查导致风险的因素 赋予复原力，希望减少残疾和疾病发生率。 抗衰老和长寿基因，在细胞代谢、中枢神经系统中发挥关键作用 这个提议的关键是 KLOTHO 似乎也 增强突触完整性并防止神经变性，因此，这种综合性的临床治疗。 相关项目将严格调查 KLOTHO 1) 是否具有抗衰老能力 和 AD 相关的突触功能障碍，并且 2) 改变此类功能障碍之间的关系 拟议的研究将是横向和纵向的认知能力下降。 嵌入两个特征明确且纵向遵循的强大框架内 大约 2,000 名高危中年成年人队列（威斯康星州阿尔茨海默病登记处） 预防 [WRAP] 和威斯康星阿尔茨海默病研究中心 [WADRC]）。 参与者已经进行了 KLOTHO 基因分型，并且已经进行了认知表型长达 WRAP/WADRC 下的 20 年 R01 将为这些参与者的一部分提供资源。 (N=150) 接受多模式生物标志物评估（[11C]UCB-J PET 成像、CSF 和 基线和 2 年随访时的血液生物标志物）。 为预防大脑/认知提供宝贵的见解和药物靶点的潜力 随着年龄的增长或 AD 病理负担而恶化。