Behavioral and Molecular Consequences of Tau Pathology in Locus Coeruleus in Prodromal Alzheimer's Disease

阿尔茨海默病前驱期蓝斑 Tau 蛋白病理学的行为和分子后果

基本信息

批准号：
10604890
负责人：
ANURADHA KORUKONDA
金额：
$ 4.77万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604890
关键词：
Ablation Adrenergic Receptor Affect Affinity Chromatography Agitation Alzheimer&apos s Disease Alzheimer&apos s disease patient American Animal Model Anxiety Arousal Attention Axonal Transport Behavior Behavior assessment Behavioral Brain Brain Stem Caregivers Cell Nucleus Cells Clinical Trials Design Cognitive Cognitive deficits Coupled DSP 4 Dementia Deposition Development Disease Disease Progression Early Diagnosis Emotional Exhibits Family Foundations Frontotemporal Dementia Functional disorder Gene Expression Genes Genetic Gliosis Goals Healthcare Systems Human Hyperactivity Immunohistochemistry Impaired cognition In Situ Hybridization Individual Learning Mediating Memory Memory impairment Mental Depression Modeling Molecular Molecular Profiling Mus Nerve Degeneration Neurobehavioral Manifestations Neurodegenerative Disorders Neurofibrillary Tangles Neurons Neurotoxins Norepinephrine Oxidative Stress Pathogenesis Pathologic Pathology Patients Pattern Phase Phenotype Physiological Processes Prosencephalon Quality of life Ribosomes Senile Plaques Signal Transduction Sleep Sleep Wake Cycle Sleep disturbances Specificity Stress Suggestion Symptoms Synaptic plasticity Techniques Technology Testing Therapeutic Therapeutic Intervention Time Transcript Transgenes Transgenic Mice Translating United States Viral Vector Work aging population anxiety-like behavior astrogliosis behavioral phenotyping beta amyloid pathology cell type common symptom diagnostic tool experience extracellular family burden hyperphosphorylated tau locus ceruleus structure memory consolidation mouse model mutant nerve supply neuroinflammation neuropathology neuropsychiatric symptom neuropsychiatry noradrenergic norepinephrine system postsynaptic preventive intervention prodromal Alzheimer&apos s disease promoter receptor density response socioeconomics targeted treatment tau Proteins tau aggregation tau mutation therapeutic development therapeutic target therapeutically effective transcriptome transcriptome sequencing transcriptomics transmission process

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is the most prevalent form of dementia, affecting 55 million worldwide, and is typified by extracellular deposits of amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Numerous clinical trials designed to alleviate cognitive symptoms by targeting Aβ pathology have failed. However, few studies have comprehensively examined the earlier, prodromal stages, which are characterized by anxiety, agitation, depression, and sleep-wake disturbances that significantly disrupt quality of life and ability to remain independent. The noradrenergic nucleus locus coeruleus (LC) modulates these physiological processes and is the first region to accumulate hyperphosphorylated ‘pretangle’ tau decades before cognitive deficits and Aβ plaques appear. It is therefore important to establish whether a causal relationship between LC tau pathology and prodromal symptoms exists because it can lead to development of therapeutic interventions that relieve these devastating non-cognitive symptoms and possibly halt disease progression. While catastrophic LC cell body degeneration occurs in late AD, the earlier prodromal phases are characterized by aberrant tau accumulation and reductions in LC innervations to projection regions. Moreover, there are suggestions that surviving LC neurons show compensatory increases in firing accompanied by elevations in forebrain adrenergic receptors, thus promoting noradrenergic hyperactivity that could underlie the prodromal symptoms. Since most animal models fail to recapitulate the pathological prodromal feature of hyperphosphorylated tau in the LC, I will develop a biologically valid mouse model where aberrant forms of tau are exclusively expressed in the LC using viral vector-mediated strategies. In Aim 1, I will determine if LC tau burden disrupts LC-sensitive behaviors relevant to prodromal symptoms and exacerbates neuropathology. In Aim 2, I will interrogate the genetic mechanisms that underlie tau-mediated LC dysregulation and degeneration by using Translating Ribosome Affinity Purification (TRAP) to selectively isolate the LC transcriptome and RNAscope in situ hybridization to assess downstream effects on adrenergic receptor gene expression in LC-projecting regions. I hypothesize that aberrant tau in the LC will cause behavioral abnormalities that are commonly associated with the prodromal phase of AD and disrupt normal noradrenergic transmission. Successful completion of these aims will reveal putative molecular mechanistic factors that underlie prodromal symptoms commonly experienced by AD patients and can yield disease-modifying targets for therapeutic interventions.

项目摘要阿尔茨海默氏病（AD）是痴呆症最普遍的形式，在全球范围内影响5500万，典型通过淀粉样蛋白β（Aβ）斑块和细胞内Tau神经原纤维缠结的细胞外沉积。许多临床旨在通过靶向Aβ病理来减轻认知症状的试验失败了。但是，很少有研究全面检查了较早的前驱阶段，其特征是焦虑，激动，抑郁症和睡眠止境会严重破坏生活质量和留下的能力独立的。去甲肾上腺素核基因座（LC）调节这些物理过程，IS 在认知缺陷和Aβ之前数十年来积累过度磷酸化的“ pripangle” tau的第一个区域斑块出现。因此，重要的是确定LC Tau病理学之间的因果关系是否存在并且存在前驱症状，因为它可以导致拯救理论干预的发展这些毁灭性的非认知症状和可能的停止疾病进展。而灾难性的LC细胞身体变性发生在AD后期，较早的前驱相具有异常的特征 LC对投影区域的累积和减少。而且，有建议幸存的LC神经元显示出通过前脑肾上腺升高完成的射击的补偿性增加受体，从而促进了可能是前驱症状的基础的肾上腺素过度活跃性。自大多数动物模型未能概括LC中高磷酸化TAU的病理前驱特征，我将开发一个具有生物学有效的鼠标模型，其中专门在LC中使用异常形式的tau形式病毒媒介介导的策略。在AIM 1中，我将确定LC Tau Burnen是否会破坏LC敏感的行为与前驱症状有关，并加剧神经病理学。在AIM 2中，我将审问遗传 Tau介导的LC失调和变性的机制通过使用翻译核糖体亲和力纯化（TRAP）选择性地隔离LC转录组和原位杂交评估对LC投射区域中肾上腺素受体基因表达的下游影响。我假设这一点 LC中的异常Tau会引起通常与前驱物相关的行为异常 AD的阶段和破坏正常的去甲肾上腺素能传播。这些目标的成功完成将揭示 AD患者常见的前驱症状是基本的推定分子机理因素并可以产生用于治疗干预措施的疾病改良靶标。