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

项目摘要 阿尔茨海默病（AD）是痴呆症的最普遍形式，影响全世界5500万人，并且典型地表现为 淀粉样蛋白-β（Aβ）斑块的细胞外沉积和细胞内tau神经元缠结。许多临床 旨在通过靶向Aβ病理学来缓解认知症状的试验已经失败。然而，很少有研究 全面检查了早期的前驱阶段，其特征是焦虑，激动， 抑郁症和睡眠-觉醒障碍，严重影响生活质量和保持 独立的去甲肾上腺素能核蓝斑（LC）调节这些生理过程， 在认知缺陷和Aβ之前几十年， 出现斑块。因此，重要的是要确定LC tau病理学之间是否存在因果关系 前驱症状的存在是因为它可以导致治疗干预的发展， 这些毁灭性的非认知症状，并可能阻止疾病的进展。虽然灾难性的LC单元 AD晚期出现体变性，早期前驱期以异常tau蛋白为特征， LC神经支配向投射区域的累积和减少。此外，有人建议， 存活的LC神经元表现出代偿性放电增加，伴随着前脑肾上腺素能神经元的升高。 受体，从而促进去甲肾上腺素能亢进，可能是前驱症状的基础。由于大多数 动物模型不能概括LC中过度磷酸化tau蛋白的病理前驱特征，我将 开发生物学上有效的小鼠模型，其中异常形式的tau仅在LC中表达， 病毒载体介导的策略。在目标1中，我将确定LC tau负荷是否会破坏LC敏感性行为 与前驱症状相关并加重神经病理学。在目标2中，我将询问基因 使用翻译核糖体研究tau介导的LC失调和变性的机制 亲和纯化（TRAP）选择性分离LC转录组和RNAscope原位杂交， 评估对LC投射区肾上腺素能受体基因表达的下游影响。我假设 LC中异常的tau蛋白会导致行为异常， AD阶段并破坏正常的去甲肾上腺素能传递。成功完成这些目标将揭示 AD患者通常经历的前驱症状的潜在分子机制因素 并且可以产生用于治疗干预的疾病修饰靶点。

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.