Local and global consequences of hyperphosphorylated tau in the locus coeruleus in Alzheimer's Disease

阿尔茨海默病蓝斑中过度磷酸化 tau 蛋白的局部和整体后果

• 批准号: 10457464
• 负责人: Michael Kelberman
• 金额: $ 4.68万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457464
• 关键词: Age; Aggressive behavior; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amygdaloid structure; Amyloid beta-Protein; Amyloid deposition; Animal Model; Anxiety; Appearance; Arousal; Attention; Attenuated; Behavior; Behavioral; Biological Models; Brain; Brain region; Cause of Death; Cell Nucleus; Cells; Clinic; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Communication; Data; Dementia; Deterioration; Development; Disease; Economics; Electrophysiology (science); Emotional; Exhibits; Family Caregiver; Female; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genetic; Goals; Health; Hippocampus (Brain); Human; Human Amyloid Precursor Protein; Impaired cognition; Intervention; Learning; Length; Mediating; Mediator of activation protein; Memory impairment; Morphology; Neurites; Neurobehavioral Manifestations; Neurofibrillary Tangles; Neurons; Norepinephrine; Pathogenicity; Pathology; Patients; Pattern; Persons; Pharmacology; Phase; Physiological; Physiology; Population; Property; Prosencephalon; Rattus; Rest; Rodent; Senile Plaques; Signal Transduction; Site; Societies; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Organisms; Translating; United States; Ursidae Family; Virus; Work; abeta deposition; age related; aged; base; behavior influence; biological adaptation to stress; connectome; density; experimental study; extracellular; familial Alzheimer disease; flexibility; hyperphosphorylated tau; in vivo; insight; interest; locus ceruleus structure; male; mutant; nerve supply; neuron loss; neuropathology; noradrenergic; norepinephrine system; novel therapeutics; optogenetics; pre-clinical; presenilin-1; promoter; relating to nervous system; response; tau Proteins; tau aggregation; tau expression; tau mutation; therapeutic target; transmission process

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common form of dementia world-wide, afflicting nearly 46 million people. The two hallmark AD pathologies are extracellular β-amyloid (Aβ) plaques and intracellular aggregated tau, termed neurofibrillary tangles. Many treatments that target amyloid deposition in mid to late stages of disease are effective in animal models but have failed in clinical trials. However, recent evidence indicates that hyperphosphorylated “pre-tangle” tau in the noradrenergic locus coeruleus (LC) appears decades prior to cognitive symptoms and Aβ deposition, offering fresh insight into the potential cause and progression of AD. The LC coordinates distinct brain states through norepinephrine release at target sites, and many LC-modulated behaviors go awry in AD, but few studies have directly investigated the consequences of aberrant tau on LC function. Aberrant tau expression causes hypoactivity in neurons, and tau load is associated with blunted novelty response, a key behavior influenced by LC activity. Furthermore, the LC does not exhibit frank neuronal loss until late stages of disease when cognitive decline is evident, but neuron morphology is altered, and innervation density is decreased at early stages of disease. Despite these potentially pathogenic changes, our data indicates that activation of the LC has the potential to restore normal cognition. In TgF344-AD transgenic rats, similar to humans, hyperphosphorylated tau appears in the LC prior to tau or Aβ pathology in the forebrain. Importantly, chemogenetic activation of the LC is effective at rescuing spatial learning deficits in aged TgF344-AD rats, indicating that LC stimulation enhances cognition even in the presence of AD-like neuropathology in the LC and forebrain. However, there is no information regarding the effects of tau on LC physiology or LC-induced changes in brain-wide functional connectivity. In this proposed project, I will use TgF344-AD rats to assess both tau-mediated LC neuron dysfunction and the therapeutic potential of LC stimulation to correct functional connectome deterioration. In Aim 1, I will use in vivo electrophysiology to determine whether hyperphosphorylated tau in the LC can alter neuron firing rates in an age-dependent manner. In Aim 2, I will combine optogenetic stimulation of the LC with simultaneous functional magnetic resonance imaging to assess whether LC stimulation can rescue brain-wide network functional connectivity deficits. I hypothesize that aberrant tau will decrease neuron firing rates in an age- dependent manner that will be paralleled by gradual, brain-wide hypoconnectivity, which will be corrected by optogenetic LC stimulation. Completion of these aims will determine the functional consequences of the earliest known AD pathology, hyperphosphorylated tau in the LC, and facilitate development of LC-NE based therapeutic interventions to retard progression.

项目摘要 阿尔茨海默氏病（AD）是世界范围内最常见的痴呆症形式，困扰着近4600万人 人AD的两个标志性病理是细胞外β-淀粉样蛋白（Aβ）斑块和细胞内聚集的β-淀粉样蛋白（Aβ）斑块。 tau蛋白，称为神经元缠结。许多针对疾病中晚期淀粉样蛋白沉积的治疗方法 在动物模型中有效，但在临床试验中失败。然而，最近的证据表明， 去甲肾上腺素能蓝斑（LC）中过度磷酸化的“前缠结”tau蛋白出现在 认知症状和Aβ沉积，为AD的潜在病因和进展提供了新的见解。的 LC通过在靶部位释放去甲肾上腺素来协调不同的大脑状态，并且许多LC调节的 行为在AD中出错，但很少有研究直接研究异常tau蛋白对LC的影响 功能异常的tau蛋白表达导致神经元活动减退，tau蛋白负荷与迟钝的新奇感有关 反应，受LC活性影响的关键行为。此外，LC没有表现出明显的神经元损失 直到疾病晚期，此时认知能力明显下降，但神经元形态发生改变， 密度在疾病的早期阶段降低。尽管有这些潜在的致病性变化，我们的数据表明， 激活LC有可能恢复正常认知。在TgF 344-AD转基因大鼠中，类似于 在人类中，过度磷酸化的tau在前脑中tau或Aβ病理学之前出现在LC中。重要的是， LC的化学发生激活在挽救老年TgF 344-AD大鼠的空间学习缺陷方面是有效的， 表明LC刺激增强认知，即使在LC中存在AD样神经病理学， 前脑然而，没有关于tau对LC生理学或LC诱导的变化的影响的信息 在全脑的功能连接中。 在这个提议的项目中，我将使用TgF 344-AD大鼠来评估tau蛋白介导的LC神经元功能障碍， 以及LC刺激纠正功能性连接体退化的治疗潜力。在目标1中，我将使用 体内电生理学以确定LC中过度磷酸化的tau是否可以改变神经元放电速率 以年龄依赖的方式。在目标2中，我将联合收割机结合LC的光遗传学刺激， 功能性磁共振成像评估LC刺激是否可以拯救全脑网络 功能性连接缺陷。我假设异常的tau蛋白会降低神经元的放电率- 依赖的方式，将被逐渐的，全脑的连接不足所取代，这将被纠正， 光遗传学LC刺激。这些目标的完成将决定最早的 已知的AD病理，LC中过度磷酸化的tau，并促进基于LC-NE的治疗药物的开发 干预以延缓进展。

项目成果

A novel link between locus coeruleus activity and amyloid-related cognitive decline.

基因座二聚体活性与淀粉样蛋白相关的认知下降之间的新联系。

• DOI: 10.1016/j.tins.2022.05.006
• 发表时间: 2022-09
• 期刊: TRENDS IN NEUROSCIENCES
• 影响因子: 15.9
• 作者: Kelberman, Michael A.;Weinshenker, David
• 通讯作者: Weinshenker, David

What's That (Blue) Spot on my MRI? Multimodal Neuroimaging of the Locus Coeruleus in Neurodegenerative Disease.

• DOI: 10.3389/fnins.2020.583421
• 发表时间: 2020
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Kelberman M;Keilholz S;Weinshenker D
• 通讯作者: Weinshenker D

Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease.

阿尔茨海默病转基因大鼠模型中蓝斑放电的年龄依赖性失调。

• DOI: 10.1016/j.neurobiolaging.2023.01.016
• 发表时间: 2023
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Kelberman,MichaelA;Rorabaugh,JackiM;Anderson,ClaireR;Marriott,Alexia;DePuy,SethD;Rasmussen,Kurt;McCann,KatharineE;Weiss,JayM;Weinshenker,David
• 通讯作者: Weinshenker,David