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Determining the Roles of Aging and Extrasynaptic NMDARs in Tau Pathology.

确定衰老和突触外 NMDAR 在 Tau 病理学中的作用。

基本信息

批准号：
8878717
负责人：
Miranda Nicole Reed
金额：
$ 35.52万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878717
关键词：
Academic Research Enhancement Awards Age-Months Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Applications Grants Area Award Behavioral Binding Proteins Biochemistry Biomedical Research CREB1 gene Cell Death Collaborations Communities Core Facility Data Analyses Dendritic Spines Development Environment Equilibrium Event Exhibits Faculty Foundations Funding Future Goals Grant Human In Vitro Laboratory Animals Location Mediating Memory Memory Loss Memory impairment Methods Microtubules Mus Mutation N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurofibrillary Tangles Neurosciences Pathology Pathway interactions Proteins Psychology Receptor Signaling Research Research Personnel Risk Factors Role Science Short-Term Memory Statistical Methods Students Synapses Tauopathies Testing Toxic effect Training Transgenes United States National Institutes of Health Universities West Virginia Work age effect age related aged aging brain base career cytotoxicity design experience graduate student hyperphosphorylated tau in vivo innovation insight long term memory mouse model neurotoxicity novel overexpression programs progressive neurodegeneration public health relevance receptor src-Family Kinases tau Proteins tau expression tau phosphorylation trafficking transcription factor undergraduate student

项目摘要

DESCRIPTION (provided by applicant): Tau is the main component of neurofibrillary tangles observed in Alzheimer's disease and other related neurodegenerative tauopathies, and aging is the greatest known risk factor for Alzheimer's disease. We propose here a novel mechanism by which tau and aging may interact. The objective of the current proposal, in the context of a R15 grant mechanism, is to investigate the role of extrasynaptic NMDA receptors (NMDARs) in tau- and age- related memory deficits. Activation of extrasynaptic NMDARs is associated with neurotoxicity by stimulating cell death pathways, and blockade of these receptors reduces tau hyperphosphorylation, an early pathological signature of Alzheimer's disease. The central hypothesis of this application is that tau hyperphosphorylation increases the number of extrasynaptic NMDARs that then further increase tau phosphorylation, leading to a vicious, positive feedforward loop. We hypothesize that an aged brain is more vulnerable to this cycle due to an age-related increase in the activity and number of extrasynaptic NMDARs. Specific aims of this study are to: 1. determine how an aged brain exacerbates tau pathology and memory deficits, 2. identify the in vivo consequences of aging and tau on the number of extrasynaptic NMDARs, and 3. test the hypothesis that decreasing extrasynaptic NMDAR activity will rescue memory deficits in a tau mouse model of Alzheimer's disease by decreasing tau pathology. The innovative aspects of this proposal lie in the use of (1) regulatable mouse models in which tau expression can be suppressed until mice have aged, allowing us to study the effects of aging independently of prolonged tau expression, and (2) an incredibly sensitive, longitudinal memory test with a large dynamic range, allowing us to detect subtle differences between young and aged mice. An equally important feature of the project is the training opportunities that it provides for undergraduate and graduate researchers, who will plan studies, work with laboratory animals, collect and analyze data, and present their work to the scientific community (with trips funded by WVU). The project spans many areas, including psychology, biochemistry, and neuroscience, and should, therefore, attract an array of students. The diversity of the project should also promote collaborations between students and faculty from different departments and the IDeA-funded core facilities on campus. Receipt of an AREA award will have a profound effect on the newly established Behavioral Neuroscience program in the Psychology Department at West Virginia University, by increasing the quality and quantity of opportunities for student research in biomedical science. As a young and early career investigator, an award would also support the PI's efforts to establish an independent, productive research program and will establish a foundation for further participation in NIH programs in the future.

描述(申请人提供)：tau是阿尔茨海默病和其他相关神经退行性疾病中观察到的神经原纤维缠结的主要成分，而衰老是阿尔茨海默病的最大已知风险因素。我们在这里提出了一种新的机制，通过这种机制，tau可以与衰老相互作用。本提案的目的是在R15授予机制的背景下，研究突触外NMDA受体(NMDAR)在tau和年龄相关记忆缺陷中的作用。突触外NMDAR的激活通过刺激细胞死亡途径与神经毒性有关，阻断这些受体可以减少tau过度磷酸化，tau过度磷酸化是阿尔茨海默病的早期病理特征。这一应用的中心假设是tau的过度磷酸化增加了突触外NMDAR的数量，然后进一步增加了tau的磷酸化，导致了一个恶性的、正的前馈循环。我们假设，衰老的大脑更容易受到这种循环的影响，这是因为与年龄相关的突触外NMDAR的活动和数量增加。这项研究的具体目的是：1.确定衰老的大脑如何加剧tau病理和记忆缺陷，2.确定衰老和tau对突触外NMDAR数量的体内影响，以及3.验证这样的假设，即减少突触外NMDAR活动将通过减少tau病理来挽救阿尔茨海默病tau小鼠模型的记忆缺陷。这一建议的创新之处在于使用了(1)可调节的小鼠模型，在该模型中，tau的表达可以被抑制，直到小鼠衰老，使我们能够研究衰老的影响，而不是依赖于tau的长时间表达，以及(2)令人难以置信的敏感的、具有大动态范围的纵向记忆测试，使我们能够检测出年轻和老年小鼠之间的细微差异。该项目的一个同样重要的特点是它为本科生和研究生研究人员提供了培训机会，他们将计划研究，与实验室动物合作，收集和分析数据，并向科学界展示他们的工作(旅行由西弗吉尼亚大学资助)。该项目涉及许多领域，包括心理学、生物化学和神经科学，因此应该会吸引一大批学生。该项目的多样性还应该促进来自不同系的学生和教职员工之间的合作，以及由IDEA资助的校园核心设施。获得AREA奖将对西弗吉尼亚大学心理学系新设立的行为神经科学项目产生深远影响，因为它增加了学生在生物医学科学领域进行研究的机会的质量和数量。作为一名年轻的职业研究人员，获奖还将支持PI建立一个独立的、富有成效的研究计划的努力，并将为未来进一步参与NIH计划奠定基础。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of an α5GABAA inverse agonist on MK-801-induced learning deficits in an incremental repeated acquisition task.

α5GABAA 反向激动剂对增量重复采集任务中 MK-801 诱导的学习缺陷的影响。

DOI：
10.1097/fbp.0000000000000053
发表时间：
2014
期刊：
Behavioural pharmacology
影响因子：
1.6
作者：
Povroznik,JessicaM;Rudy,CarolynC;Hunsberger,HollyC;Tosto,DavidE;Reed,MirandaN
通讯作者：
Reed,MirandaN

Alterations in Hippocampal Activity and Alzheimer's Disease.

DOI：
10.1037/tps0000124
发表时间：
2017-12
期刊：
Translational issues in psychological science
影响因子：
1.8
作者：
Setti SE;Hunsberger HC;Reed MN
通讯作者：
Reed MN

Peripherally restricted viral challenge elevates extracellular glutamate and enhances synaptic transmission in the hippocampus.

外周限制的病毒攻击会升高细胞外谷氨酸并增强海马体中的突触传递。

DOI：
10.1111/jnc.13665
发表时间：
2016
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
Hunsberger,HollyC;Wang,Desheng;Petrisko,TiffanyJ;Alhowail,Ahmad;Setti,SharayE;Suppiramaniam,Vishnu;Konat,GregoryW;Reed,MirandaN
通讯作者：
Reed,MirandaN

Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression.

DOI：
10.1111/jnc.13230
发表时间：
2015-10
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
Hunsberger HC;Weitzner DS;Rudy CC;Hickman JE;Libell EM;Speer RR;Gerhardt GA;Reed MN
通讯作者：
Reed MN

Riluzole rescues alterations in rapid glutamate transients in the hippocampus of rTg4510 mice.

Riluzole 可挽救 rTg4510 小鼠海马中快速谷氨酸瞬变的改变。