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：
10396654
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/10396654
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 Amyloid beta-Protein Precursor 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 (Brain)Human Amyloid Precursor Protein Impairment Intercellular Fluid Lead Maintenance Mediating Memory Memory impairment Microdialysis Mus Neurons Pathology Peptides Pharmacology Phase Property Proteins 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 base daily functioning design designer receptors exclusively activated by designer drugs improved in vivo insight interstitial memory consolidation mouse model mutant neuron loss neurotoxic novel novel therapeutic intervention poor sleep public health relevance restoration 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.

项目摘要睡眠障碍预测阿尔茨海默氏病（AD）的风险。睡眠效果周期严格调节大脑 aβ和tau的间质液（ISF）水平，两种积累在AD中的临界蛋白。 Aβ和Tau都是由神经元活动发布，在清醒期间比睡眠更高。而且，睡眠是关键阶段在其中从大脑中清除ISF中的因素。因此，睡眠障碍每天影响功能，也有助于疾病进展。但是，关于哪些大脑区域的了解知之甚少在广告中受到影响以引起睡眠障碍，因此难以确定电路水平机制驱动功能障碍或设计有针对性的治疗策略。该项目检验了以下假设丘脑网状核（TRN）是AD的关键大脑区域，其活性障碍驱动睡眠干扰和加剧疾病进展。 TRN是丘脑皮质的主要组成部分调节睡眠，注意力和记忆的皮质丘脑网络都受到AD的影响。然而，对于AD患者或动物模型中的TRN状态知之甚少。我们发现在转基因小鼠中表达突变的人淀粉样蛋白前体蛋白（APP小鼠），TRN活性大大降低缺乏细胞损失。 TRN活性的这种减少导致睡眠碎片和慢波减少睡眠（SWS），并预测海马和皮质中Aβ沉积的大小，这可能有关事实是，SWS是睡眠阶段，在该阶段降低了活性依赖性Aβ，而Aβ的阶段从大脑中清除。此外，在APP中的疾病早期在SWS和睡眠维持中定义在海马缺陷之前，小鼠表明TRN损伤可能会预测并有助于疾病进展。该建议的目标是确定损害TRN活性的细胞机制，并测试TRN中有选择性操纵神经元活性是否可以使睡眠正常化，减少Aβ的积累，并改善记忆。为了实现这些目标，在AIM 1中，我们将使用电生理学和药理学丘脑切片以识别TRN的固有，突触和网络性能，从而导致其在应用小鼠。在AIM 2中，我们将使用Dreadds急性激活App小鼠中的TRN细胞以测试TRN是否激活影响间质Aβ和/或记忆巩固的动力学。在AIM 3中，我们将使用Dreadd介导的 APP小鼠中TRN激活以测试TRN的慢性激活是否可以使睡眠参数归一化，请降低Aβ 积累并改善记忆力。该项目的结果将产生重大影响，因为它们：1）突出显示疾病早期的脆弱网络，可能预测并导致疾病进展，2）确定新型的治疗策略，有可能使睡眠正常，改善记忆力并延迟疾病进展获得的见解也将用于得出有关动态的一般原则广告相关的蛋白质（例如Aβ和TAU）在大脑中，这将影响我们治疗这种复杂疾病的能力。