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.

项目概要/摘要 人类寿命延长的一个不幸后果是与衰老相关的神经退行性疾病 阿尔茨海默病 (AD) 等疾病是导致认知能力下降的最大风险因素。 AD 就是衰老，但我们对衰老如何使大脑容易产生这些后果缺乏了解。 与认知功能障碍相关的突触改变在正常和病理中都很普遍 衰老，尽管它们彼此不同 在正常衰老中，影响神经元的微妙突触变化。 功能性谷氨酸能受体的数量导致突触功效下降并导致认知障碍 在 AD 中，突触损失先于细胞死亡，并且是与 AD 相关的神经病理学特征。 突触变化无疑是正常现象的一个重要特征。 衰老和病理性神经变性，以及与认知能力下降的明显联系强调了重要性 同时研究非人类灵长类动物（NHP）的这些衰老特征。 神经解剖学、神经生理学和人类认知能力，也可以发展标志 AD 的神经病理学；Tau 蛋白缠结和 β-淀粉样蛋白斑块。 狨猴（Callithrix jacchus）作为 NHP 模型，用于同时研究与衰老相关的认知衰退 与寿命较长（25-40 年）的猕猴相比，狨猴具有 平均寿命相对较短，为 9-10 年，使其可用于衰老的纵向研究。 狨猴执行海马依赖性记忆任务（延迟记忆任务）时与衰老相关的缺陷 识别跨度任务（DRST）将被确定，该任务的性能随着正常老化而下降。 与健康人相比，人类、猕猴以及患有轻度 AD 的患者在 DRST 上受到进一步损害 这项任务是使用内部的自动触摸屏系统为狨猴开发的。 该目标将测试老年动物记忆能力受损的假设。 在目标 2 中，非侵入性正电子发射断层扫描反映了与衰老相关的认知能力下降。 （PET）成像将用于测量狨猴海马突触的变化，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。 目标将检验老年狨猴海马体示踪剂吸收减少的假设，反映 与年轻动物相比，AMPA 受体密度降低，此外，还会有强烈的阳性反应。 AMPA 受体密度与认知表现之间的相关性，通过目标 1 中的 DRST 进行测量。 建立这个实验平台来同时跟踪衰老相关的变化 海马依赖性记忆和 AMPA 受体密度将使未来的纵向研究能够 阐明狨猴大脑中突触变化和认知能力下降的时间过程。 导致在临床症状出现之前预测神经变性发作的新方法。