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：
10058690
负责人：
Michael Beierlein
金额：
$ 75.8万
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/10058690
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 therapeutics 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.

项目概要睡眠障碍可预测阿尔茨海默病 (AD) 的风险。睡眠-觉醒周期对大脑具有重要调节作用。间质液 (ISF) 中 Aβ 和 tau 的水平，Aβ 和 tau 是 AD 中积累的两种关键蛋白质。由神经活动释放，清醒时释放的释放量高于睡眠时释放的释放量。此外，睡眠也是一个关键因素。 ISF 中的因子从大脑中清除的阶段因此，睡眠障碍会影响日常生活。功能，也有助于疾病进展。然而，我们对哪些大脑区域知之甚少。 AD 中受到影响而引起睡眠障碍，因此很难确定导致睡眠障碍的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测试了以下假设：丘脑网状核 (TRN) 是 AD 的关键大脑区域，其活动受损会导致睡眠 TRN 是丘脑皮质的主要组成部分。调节睡眠、注意力和记忆力的皮质丘脑网络在 AD 中都会受到影响。我们对 AD 患者或动物模型中的 TRN 状态知之甚少，但我们在转基因小鼠中发现了这一点。表达突变型人类淀粉样前体蛋白（APP 小鼠），TRN 活性显着降低， TRN 活性的减少导致睡眠碎片化和慢波减少。睡眠（SWS），并预测了海马和皮质中 Aβ 沉积的程度，这可能与事实上，SWS 是睡眠阶段，在此期间，活动依赖性 Aβ 的产生减少，并且 Aβ 此外，SWS 和睡眠维持缺陷在 APP 疾病早期就表现出来。小鼠，在海马缺陷之前，表明 TRN 损伤可能既预测又有助于该提案的目标是确定损害 TRN 活性的细胞机制，并测试选择性操纵 TRN 中的神经活动是否可以使睡眠正常化、减少 Aβ 积累，为了实现这些目标，在目标 1 中，我们将使用电生理学和药理学。丘脑切片来识别 TRN 的内在、突触和网络特性，这些特性导致其在在目标 2 中，我们将使用 DREADD 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 的动态和/或记忆巩固在目标 3 中，我们将使用 DREADD 介导的。在 APP 小鼠中激活 TRN，以测试 TRN 的慢性激活是否可以使睡眠参数正常化、减少 Aβ 积累，并提高记忆力。该项目的结果将产生重大影响，因为它们：1) 突出疾病早期的脆弱网络可以预测并促进疾病进展，2）确定具有使睡眠正常化、改善记忆力和延缓疾病进展的潜力的新型治疗策略所获得的见解也将用于得出有关阿尔茨海默病动力学的一般原则。大脑中与 AD 相关的蛋白质，如 Aβ 和 tau 蛋白，将影响我们治疗这种复杂疾病的能力。