权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Thalamic Reticular Nucleus Dysfunction in Alzheimer's Disease

阿尔茨海默病中的丘脑网状核功能障碍

基本信息

批准号：
10612400
负责人：
Michael Beierlein
金额：
$ 66.3万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612400
关键词：
Abeta clearance Abeta synthesis Acute Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Animal Model Attention Behavior Brain Brain region Cell Nucleus Cells Chronic Cognition Cognitive Cognitive deficits Complex Deposition Disease Disease Progression Disinhibition Electrophysiology (science)Exhibits Functional disorder Goals Hippocampus Human Amyloid Precursor Protein Impairment Intercellular Fluid Lead Maintenance Mediating Memory Memory impairment Microdialysis Mus Neurons Pathology Peptides Pharmacology Phase Property Proteins Seizures Sleep Sleep Architecture Sleep Deprivation Sleep Fragmentations Sleep Wake Cycle Sleep disturbances Slice Slow-Wave Sleep Synapses Testing Thalamic structure Therapeutic Transgenic Mice Viral Wakefulness abeta accumulation abeta deposition daily functioning design designer receptors exclusively activated by designer drugs improved improvement on sleep in vivo insight interstitial memory consolidation mouse model mutant neuron loss neurotoxic novel novel therapeutic intervention poor sleep public health relevance restoration risk prediction targeted treatment tau Proteins

项目摘要

PROJECT SUMMARY Sleep disturbances predict risk of Alzheimer’s disease (AD). Sleep-wake cycles critically regulate brain interstitial fluid (ISF) levels of Aβ and tau, two critical proteins that accumulate in AD. Both Aβ and tau are released by neuronal activity, which is higher during wakefulness than in sleep. Moreover, sleep is a critical phase during which factors in the ISF are cleared from the brain. Therefore, sleep disturbances affect daily function and also contribute to disease progression. However, little is known about which brain regions are affected in AD to give rise to sleep disturbances, making it difficult to identify the circuit level mechanisms that drive dysfunction, or to design targeted therapeutic strategies. This project tests the hypothesis that the thalamic reticular nucleus (TRN) is a critical brain region in AD, and that impairments in its activity drive sleep disturbances and exacerbate disease progression. The TRN is a major component of the thalamocortical- corticothalamic network that regulates sleep, attention, and memory, which are all affected in AD. However, little is known about the state of TRN in AD patients or in animal models. We found that in transgenic mice expressing mutant human amyloid precursor protein (APP mice), TRN activity is strikingly reduced, in the absence of cell loss. Such reductions in TRN activity led to sleep fragmentation and reductions in slow wave sleep (SWS), and predicted the magnitude of Aβ deposition in both hippocampus and cortex, which may relate to the fact that SWS is the phase of sleep during which activity-dependent production of Aβ is reduced, and Aβ is cleared from the brain. Moreover, deficits in SWS and sleep maintenance manifest early in disease in APP mice, prior to hippocampal deficits, suggesting that TRN impairment may both predict and contribute to disease progression. The goals of this proposal are to identify cellular mechanisms that impair TRN activity, and test if selectively manipulating neuronal activity in the TRN can normalize sleep, reduce Aβ accumulation, and improve memory. To achieve these goals, in Aim 1 we will use electrophysiology and pharmacology in thalamic slices to identify the intrinsic, synaptic, and network properties of TRN that result in its hypoactivity in APP mice. In Aim 2, we will use DREADDs to acutely activate TRN cells in APP mice to test if TRN activation affects dynamics of interstitial Aβ, and/or memory consolidation. In Aim 3, we will use DREADD-mediated activation of TRN in APP mice to test if chronic activation of TRN can normalize sleep parameters, reduce Aβ accumulation, and improve memory. Results from this project will have major impact because they: 1) highlight a vulnerable network early in disease that may predict and contribute to disease progression, and 2) identify a novel therapeutic strategy with potential to normalize sleep, improve memory, and delay disease progression in Alzheimer’s disease. Insights gained will also be used to derive general principles about the dynamics of AD-related proteins like Aβ and tau in the brain, which will impact our ability to treat this complex disease.

项目总结： -- 睡眠障碍可以预测患阿尔茨海默氏症(AD)的风险。睡眠-唤醒周期对大脑的调节至关重要。间质中的ββ和Ttau是两种在AD中积聚的关键蛋白质，它们的水平都是。这是由神经元的神经活动释放出来的，这种活动在清醒时比在睡眠中更高。此外，睡眠时间也是一个非常关键的因素。在这一阶段中，大脑中的各种因素都会被清除。因此，睡眠和干扰会影响日常生活。功能障碍也有助于疾病的进展。然而，关于大脑的哪些区域是什么，人们知之甚少。在公元6月份，受影响的人可能会因为睡眠和干扰而增加，这使得他们很难确定这一问题的主要电路和机制。推动功能障碍，即设计有针对性的治疗药物策略。这个新项目将测试支持这一理论的假说。丘脑-中脑网状核团(TRN)是AD的一个重要脑区，它会损害大脑的正常活动，从而驱动睡眠。干扰会加剧疾病的进展。TRN是丘脑皮质的一个主要组成部分。皮质丘脑神经网络负责调节睡眠、注意力、运动和记忆，这些都可能在AD中受到影响。然而，对于在AD患者中发现或在其他动物模型中死亡的患者的TRN基因的状态，我们还知之甚少。我们已经在转基因小鼠中发现了这种基因。在表达突变的人淀粉样蛋白前体蛋白(APP)小鼠后，TRN的活性显著降低，尤其是在小鼠。由于没有细胞丢失，这种减少导致TRN的活动导致他们睡不着，因为碎片化而睡不着，在一个缓慢的浪潮中减少。睡眠监测(SWS)，研究人员和研究人员预测，β在大脑海马区和大脑皮质中沉积的幅度可能会很大，这可能与此相关。为了说明这样一个事实，即SWS正处于睡眠的第一阶段，在此期间，Aββ的活动依赖型生产成本将大幅减少。这是从大脑中清除的。此外，SWS功能和睡眠与维护功能的缺陷可能在应用程序中表现为疾病的早期症状。小鼠是海马区功能缺陷的先驱，这表明TRN功能障碍可能无法预测其功能，也可能对此做出贡献。疾病和进展。这项新提案的主要目标是进一步确定可能损害TRN基因活性的细胞调控机制。并测试如果有选择地操纵神经元胞内活动，是否能使睡眠正常化，或减少β的蓄积。并改善记忆力。为了更好地实现这些目标，我们将继续使用电生理学技术和现代药理学技术。丘脑切片用于进一步识别TRN的固有、突触、神经和神经网络的特性，这些特性可能导致其在临床上表现为活动不足。小鼠应用程序。在Aim 2中，我们将使用DREADS来紧急激活小鼠应用程序中的TRN细胞，以测试是否有TRN激活。影响间质β的动态变化，影响和/或记忆的巩固。在目标3中，我们将不使用DREADD介导的。 APP中Ttrn基因在小鼠体内的激活状态是为了测试它的慢性激活状态是否能使睡眠参数正常化，从而降低Aβ。积累、学习和学习改善记忆力。从今年的项目评估中得出的结果将不会产生重大的影响，因为它们：1)将突出。一个易受攻击的疾病网络可能无法预测疾病的早期进展，也可能有助于疾病的进展，因此无法确定疾病的类型。新颖的治疗性睡眠策略具有使睡眠正常化、改善记忆力、减少和延缓疾病进展的潜在价值。在阿尔茨海默氏症中，我们所获得的洞察力也将被用来推导关于疾病动力学的一般原理。与AD相关的蛋白质，如大脑中的Aβ蛋白和A tau蛋白，将影响我们治疗这种复杂疾病的能力。