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Impact of locus coeruleus-derived tau pathology in a rodent model of early Alzheimer's disease

蓝斑源性 tau 蛋白病理学对早期阿尔茨海默病啮齿动物模型的影响

基本信息

批准号：
10343774
负责人：
Shella D Keilholz
金额：
$ 45.97万
依托单位：
EMORY UNIVERSITY
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：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343774
关键词：
Affect Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Animals Anti-Inflammatory Agents Anxiety Disorders Area Arousal Attention Behavior Behavioral Paradigm Brain Brain region Cell Nucleus Clinical Trials Cognition Cognitive Data Dementia Depressed mood Diagnostic Disease Progression Disease model Early treatment Elderly Electrophysiology (science)Faculty Functional Magnetic Resonance Imaging Functional disorder Goals Healthcare Systems Hippocampus (Brain)Human Human Amyloid Precursor Protein Hyperactivity Impaired cognition Inflammation Intervention Learning Lesion Mediating Memory impairment Mental Depression Morphology Nerve Degeneration Neurodegenerative Disorders Neurons Norepinephrine Pathogenicity Pathologic Pathology Patients Pattern Performance Phenotype Property Prosencephalon Psyche structure Quality of life Rattus Research Research Personnel Rest Rodent Rodent Model Seeds Senile Plaques Severities Sleep Disorders Stimulus Symptoms Testing Therapeutic Time Transgenes Transgenic Mice Transgenic Organisms Viral Viral Vector base biological adaptation to stress cognitive process entorhinal cortex experimental study extracellular frontal lobe imaging study in vivo innovation interest locus ceruleus structure loved ones mutant neurobehavioral neuroinflammation neuron loss neuropathology neuropsychiatry neurotoxicity noradrenergic norepinephrine system novel optogenetics presenilin-1 prevent prodromal Alzheimer&apos s disease promoter stressor targeted treatment tau Proteins tau aggregation tau mutation therapeutic target tool transmission process treatment strategy

项目摘要

Amyloid-β (Aβ) plaques and tau neurofibrillary tangles, as well as neuronal death, are the pathologic hallmarks of Alzheimer's disease (AD). Therapeutic efforts focused on Aβ have thus far failed, underscoring the urgent need for alternate approaches, particularly those that can target early AD. Aberrant tau in the locus coeruleus (LC), the major noradrenergic nucleus in the brain that regulates attention, arousal, stress responses, and cognition, is the earliest detectable AD-like neuropathology in the human brain, and LC degeneration is ubiquitious in later AD. Recent research indicates that early LC dysfunction may contribute to prodromal AD symptoms such as depression, anxiety, and sleep disorders, while later LC degeneration exacerbates cognitive impairment. Although these data suggest that the LC is a promising therapeutic target in AD, almost nothing known about how pathogenic tau impacts LC function and survival. We have developed a viral vector that drives the expression of wild-type human tau exclusively in LC neurons, which over time becomes hyperphosphorylated and misfolded, thus recapitulating the earliest forms of human AD. We will use this novel tool to study the consequences tau pathology in the LC. In Aim 1, we will determine the impact of different forms of aberrant tau on LC neuron morphology, survival, and local inflammation, and assess the potential of LC-derived tau pathology to spread to interconnected forebrain regions. In Aim 2, we will use in vivo electrophysiology and behavioral paradigms to evaluate how tau pathology affects LC activity and performance in neuropsychiatric and cognitive domains. In Aim 3, we will combine optogenetics and fMRI to determine how aberrant tau influences LC-forebrain functional connectivity. Completion of these aims will lay the groundwork for LC/tau-based therapies for early AD.

淀粉样蛋白-β(A-β)斑块和tau神经原纤维缠结以及神经元死亡是病理特征阿尔茨海默病(AD)。到目前为止，针对Aβ的治疗努力都失败了，这突显了需要其他方法，特别是那些可以针对早期AD的方法。蓝斑中异常的tau蛋白 (LC)，大脑中主要的去甲肾上腺素能核，调节注意力、觉醒、应激反应和认知，是人类大脑中最早可检测到的AD样神经病理，而LC变性是在公元后期无处不在。最近的研究表明，早期LC功能障碍可能与先兆AD有关抑郁、焦虑和睡眠障碍等症状，而后来的LC变性会加剧认知减损。尽管这些数据表明LC是治疗AD的一个有前途的治疗靶点，但几乎没有了解致病tau如何影响LC功能和生存。我们已经开发出一种病毒载体，驱动野生型人tau蛋白在LC神经元中的特异表达，随着时间的推移，它会变成过度磷酸化和错误折叠，从而概括了人类AD的最早形式。我们将用这本小说在LC中研究tau病理后果的工具。在目标1中，我们将确定不同异常tau的形式对LC神经元的形态、存活和局部炎症的影响，并评估其潜在的 LC衍生的tau病理扩散到相互连接的前脑区域。在目标2中，我们将在体内使用评估tau病理如何影响LC活动和表现的电生理学和行为范式在神经精神和认知领域。在目标3中，我们将结合光遗传学和功能磁共振成像来确定 Tau蛋白的异常影响LC-前脑的功能连接。这些目标的实现将奠定基础用于早期AD的LC/tau治疗。