Cognitive decline and synaptic change in the aging marmoset

项目摘要/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 例如阿尔茨海默病(AD)是一个日益沉重的负担。认知能力下降的单一最大风险因素 阿尔茨海默病正在老化，然而我们缺乏对衰老如何使大脑容易受到这些后果影响的理解。 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，细微的突触变化会影响 功能性谷氨酸能受体的数量导致突触效能降低并导致认知 拒绝。在AD中，突触丢失先于细胞死亡，是AD的神经病理特征，与 最严重的是认知功能障碍。突触变化无疑是正常的一个重要特征 衰老和病理性神经变性，以及与认知能力下降的明确联系，强调了这一点的重要性 同时研究衰老的这些特征。非人灵长类动物(NHP)也有类似的 神经解剖学、神经生理学和人类的认知能力，也能发展出标志 阿尔茨海默病的神经病理；Tau缠结和β淀粉样斑块。拟议的研究发展了共同的 恒河猴(Callithrix Jacchus)作为同时研究衰老相关认知衰退的NHP模型 以及突触的改变。与寿命较长的猕猴(25-40岁)相比，猕猴的寿命更长 相对较短的平均寿命为9-10年，使它们能够用于对衰老的纵向研究。在目标1中， 恒河猴在海马区依赖的记忆任务中表现出的衰老相关缺陷 将确定识别跨度任务(DRST)。此任务的性能会随着正常老化而下降 与健康人、猕猴和轻度AD患者相比，人类和猕猴在DRST上的损害更严重 老年对照组。这项任务是为绒猴开发的，使用的是自动触摸屏系统 动物的家笼子。这一目标将检验老年动物表现出记忆能力受损的假说。 在任务上，反映了与衰老相关的认知能力下降。在目标2中，无创正电子发射断层扫描 (PET)成像将用于测量用于治疗的绒猴海马区的突触变化 AIM 1中的认知测试。要做到这一点，将使用一种选择性地与AMPA受体结合的PET示踪剂。这 AIM将检验这一假说，即衰老的绒猴在海马区的示踪剂摄取减少，反映出 与年轻的动物相比，AMPA受体密度降低。此外，还将有一个强有力的、积极的 AMPA受体密度和认知表现之间的相关性，通过目标1中的DRST测量。 建立这一实验平台，同时跟踪两者与衰老相关的变化 海马区依赖的记忆和AMPA受体密度将使未来的纵向研究成为可能 阐明恒河猴脑内突触变化和认知功能衰退的时间进程。这可能会 导致在临床症状出现之前预测神经退行性变开始的新方法。

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.