Cognitive decline and synaptic change in the aging marmoset

衰老狨猴的认知衰退和突触变化

• 批准号: 10043859
• 负责人: JOHN H REYNOLDS
• 金额: $ 52.91万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043859
• 关键词: AMPA Receptors; Affect; Age; Aging; Alzheimer' s Disease; Animal Model; Animals; Applications Grants; Area; Binding; Brain; Breeding; Callithrix; Callithrix jacchus jacchus; Cell Death; Clinical; Cognition; Data; Dementia; Elderly; Exhibits; Exploratory/Developmental Grant; Future; Glutamates; Hippocampus (Brain); Home environment; Human; Impaired cognition; Impairment; Investigation; Lead; Learning; Life Cycle Stages; Link; Longevity; Longitudinal Studies; Macaca; Measures; Memory; Memory impairment; Modeling; Molecular Target; Monkeys; Mus; Nerve Degeneration; Neuroanatomy; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathologic; Patients; Performance; Positron-Emission Tomography; Prevention; Quality of life; Research; Risk Factors; Scanning; Senile Plaques; Study models; Symptoms; Synapses; System; Task Performances; Testing; Time; Tracer; Training; Visualization; Wild Type Mouse; Work; abeta deposition; aged; cognitive ability; cognitive performance; cognitive testing; density; improved; in vivo; juvenile animal; neuropathology; neurophysiology; nonhuman primate; normal aging; novel; pathological aging; receptor; receptor density; tau Proteins; tool; touchscreen; uptake; young adult

PROJECT SUMMARY/ABSTRACT An unfortunate consequence of increased human lifespan is that aging-related neurodegenerative diseases such as Alzheimer’s disease (AD) are a growing burden. The single greatest risk factor for cognitive decline and AD is aging, yet we lack an understanding of how aging predisposes the brain to these consequences. Synaptic alterations that correlate with cognitive dysfunction are prevalent in both normal and pathological aging, though they are distinct from one another. In normal aging, subtle synaptic changes that affect the number of functional glutamatergic receptors lead to a decrease in synaptic efficacy and result in cognitive decline. In AD, synaptic loss precedes cell death and is the neuropathological feature of AD that correlates most strongly with cognitive dysfunction. Synaptic changes are unmistakably an important feature of normal aging and pathological neurodegeneration, and the clear links to cognitive decline underscore the importance of simultaneously investigating these features of aging. Non-human primates (NHPs) have similar neuroanatomy, neurophysiology, and cognitive abilities to humans, and also can develop the hallmark neuropathologies of AD; Tau tangles and β-amyloid plaques. The proposed research develops the common marmoset (Callithrix jacchus) as a NHP model for simultaneously investigating aging-related cognitive decline and synaptic alterations. Compared to macaque monkeys with long lifespans (25-40 years), marmosets have a relatively short average lifespan of 9-10 years, enabling their use in longitudinal studies of aging. In Aim 1, aging-related deficits in marmosets’ performance of a hippocampus-dependent memory task, the Delayed Recognition Span Task (DRST), will be determined. Performance of this task declines with normal aging in humans and macaques and patients with mild AD are further impaired on the DRST compared to healthy elderly controls. This task has been developed for marmosets using an automated touch screen system within the animal’s home cage. This Aim will test the hypothesis that aged animals exhibit impaired memory capacity on the task, reflecting aging-related cognitive decline. In Aim 2, non-invasive positron emission tomography (PET) imaging will be used to measure synaptic alterations in the hippocampus of the marmosets used for cognitive testing in Aim 1. To do this, a PET tracer that selectively binds to AMPA receptors will be used. This Aim will test the hypothesis that aged marmosets have decreased tracer uptake in the hippocampus, reflecting decreased AMPA receptor density, compared to younger animals. Further, there will be a strong, positive correlation between AMPA receptor density and cognitive performance, measured via the DRST in Aim 1. Establishing this experimental platform for the simultaneous tracking of aging-related changes in both hippocampal-dependent memory and AMPA receptor density will enable future longitudinal investigations to elucidate the time course of synaptic changes and cognitive decline in the brains of marmosets. This could lead to novel ways to predict onset of neurodegeneration before clinical symptoms arise.

项目总结/摘要 人类寿命延长的一个不幸后果是，与衰老有关的神经退行性疾病 例如阿尔茨海默病（AD）是一个日益严重负担。认知能力下降的最大风险因素 而AD就是衰老，然而我们缺乏对衰老如何使大脑倾向于这些后果的理解。 与认知功能障碍相关的突触改变在正常和病理性认知障碍中普遍存在。 他们彼此之间，彼此之间，都是有区别的。在正常的衰老过程中，影响神经元的细微突触变化， 许多功能性突触能受体导致突触功效降低并导致认知功能障碍。 下降在AD中，突触丢失先于细胞死亡，并且是与AD的神经病理学特征相关的神经病理学特征。 认知功能障碍最严重。突触变化无疑是正常神经元的重要特征， 衰老和病理性神经退行性变，以及与认知能力下降的明确联系，强调了 同时研究衰老的这些特征。非人类灵长类动物（NHP）具有类似的 神经解剖学，神经生理学和人类的认知能力，也可以发展标志性的 AD的神经病理学; Tau缠结和β-淀粉样蛋白斑块。拟议的研究开发了共同的 用绒猴（Callithrix jacchus）作为NHP模型同时研究衰老相关的认知衰退 和突触改变。与寿命长（25-40年）的猕猴相比，绒猴有一个 相对较短的平均寿命为9-10年，使其能够用于衰老的纵向研究。在目标1中， 衰老相关的缺陷，在绒猴的表现，校园依赖的记忆任务，延迟 识别广度任务（DRST），将被确定。这项任务的表现随着年龄的正常增长而下降， 人类和猕猴以及轻度AD患者与健康人相比， 老年人对照组。这项任务是为绒猴开发的，使用的是一个自动触摸屏系统， 动物的笼子。这个目标将检验老年动物表现出记忆能力受损的假设 这反映了与年龄相关的认知能力下降。在目标2中，非侵入性正电子发射断层扫描 (PET)成像将被用来测量突触的变化，在海马的绒猴用于 目标1中的认知测试。为此，将使用选择性结合AMPA受体的PET示踪剂。这 目的是检验这一假设，即年老的绒猴在海马体中的示踪剂摄取减少， 与年轻动物相比，AMPA受体密度降低。此外，将有一个强大的，积极的， AMPA受体密度和认知能力之间的相关性，通过目标1中的DRST测量。 建立这一实验平台，同时跟踪衰老相关的变化， 依赖于记忆和AMPA受体密度将使未来的纵向研究， 阐明了绒猴大脑中突触变化和认知能力下降的时间过程。这可能 从而导致在临床症状出现之前预测神经变性发作的新方法。