Contribution of neuromelanin to selective vulnerability of locus coeruleus neurons in Alzheimer's disease

项目摘要 阿尔茨海默病（AD）是神经退行性疾病的最常见形式，并且是阿尔茨海默病的主要原因。 痴呆症，影响超过600万美国人。而AD的病理特征包括β-淀粉样蛋白 斑块和tau神经元缠结，过度磷酸化（“预缠结”）的tau蛋白的出现， 去甲肾上腺素能蓝斑（LC）和LC体积的损失是第一个可检测到的AD样变化， 人的大脑，并符合前驱AD症状的发作，如包括觉醒/睡眠 障碍、焦虑、抑郁和激越之前的坦率的认知障碍。灾难性LC 退化在疾病后期普遍存在，此时记忆丧失明显。这项提案的目的是回答 AD领域的两个关键问题：（1）为什么LC神经元易受发展中病理学的影响并在AD中死亡？ AD和（2）他们的功能障碍和退化如何有助于前驱症状和认知症状。 包括LC在内的儿茶酚胺神经元在表达神经黑色素（NM）方面是独特的， 由儿茶酚胺代谢物、重金属、脂质和蛋白质聚集体组成。NM是一个重要的 作为AD中LC神经元的生物标志物，NM敏感的MRI对比度用作LC完整性的代表。然而，在这方面， 由于NM不是啮齿动物自然产生的，我们对它如何制造神经元知之甚少。 在AD中脆弱我们已经开发了表达人酪氨酸酶（hTyr）的病毒载体，其驱动NM 在小鼠LC中产生。在目标1中，我们将确定NM如何影响LC完整性。在目标2中，我们将评估 NM诱导的LC放电和基因表达改变，以及这些LC功能变化如何触发 与AD的前驱症状和认知症状相关的行为。在目标3中，我们将操作各个方面 的NE合成/代谢和tau蛋白，以确定NM积累和毒性的修饰剂。完成 这些目标将首次测试NM和LC变性和功能之间的因果关系， 为预防AD中LC细胞损失以及行为和认知缺陷的新疗法奠定了基础。

Project Summary Alzheimer’s disease (AD) is the most common form of neurodegenerative disease and the leading cause of dementia, affecting over 6 million Americans. While the pathological hallmarks of AD include β-amyloid plaques and tau neurofibrillary tangles, the appearance of hyperphosphorylated (“pretangle”) tau in the noradrenergic locus coeruleus (LC) and loss of LC volume are the first detectable AD-like changes in the human brain, and coincide with the onset of prodromal AD symptoms such as including arousal/sleep disturbances, anxiety, depression, and agitation prior to frank cognitive impairment. Catastrophic LC degeneration is ubiquitous later in disease when memory loss is evident. The goal of this proposal is to answer two critical questions in the AD field: (1) Why are LC neurons vulnerable to developing pathology and dying in AD, and (2) how does their dysfunction and degeneration contribute to prodromal and cognitive symptoms. Catecholamine neurons, including the LC, are unique in their expression of neuromelanin (NM), a pigment comprised of catecholamine metabolites, heavy metals, lipids, and protein aggregates. NM is an important biomarker of LC neurons in AD, as NM-sensitive MRI contrast is used as a proxy of LC integrity. However, because NM is not naturally produced in rodents, we know very little about how it might make neurons vulnerable in AD. We have developed a viral vector expressing human tyrosinase (hTyr), which drives NM production in the mouse LC. In Aim 1, we will determine how NM affects LC integrity. In Aim 2, we will assess LC firing and gene expression alterations induced by NM, and how these changes in LC function trigger behaviors relevant to prodromal and cognitive symptoms of AD. In Aim 3, we will manipulate various aspects of NE synthesis/metabolism and tau to identify modifiers of NM accumulation and toxicity. Completion of these aims will test, for the first time, causal relationships between NM and LC degeneration and function, laying the foundation for novel therapies that prevent LC cell loss and behavioral and cognitive deficits in AD.