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)是最常见的神经退行性疾病，也是 痴呆症，影响着600多万美国人。而AD的病理特征包括β-淀粉样蛋白 斑块和tau神经原纤维缠结，过度磷酸化(椒盐)tau在 去甲肾上腺素能蓝斑(LC)和LC体积的丧失是最早可检测到的AD样改变 人脑，并与AD前驱症状的发作相吻合，如包括唤醒/睡眠 在出现明显的认知障碍之前，会出现精神障碍、焦虑、抑郁和不安。灾难性LC 当记忆力明显丧失时，退化在疾病后期普遍存在。这项提议的目标是回答 AD领域的两个关键问题：(1)为什么LC神经元容易发生病理变化并在 AD，以及(2)它们的功能障碍和变性如何导致前驱症状和认知症状。 儿茶酚胺神经元，包括LC，在其表达神经黑色素(NM)这一色素方面是独一无二的 由儿茶酚胺代谢物、重金属、脂质和蛋白质聚集体组成。网络管理是一个重要的 AD患者LC神经元的生物标志物，作为NM敏感的MRI对比度，可作为LC完整性的指标。然而， 因为NM不是在啮齿动物身上自然产生的，所以我们对它如何产生神经元知之甚少 在AD中易受攻击。我们开发了一种表达人酪氨酸酶(HTyr)的病毒载体，它驱动NM 在小鼠LC中制作。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放电和基因表达变化，以及这些变化是如何触发LC功能的 与AD的前驱症状和认知症状相关的行为。在目标3中，我们将操纵各个方面 NE合成/代谢和tau的研究，以确定NM积累和毒性的修饰物。完成 这些目标将首次检验NM和LC退变和功能之间的因果关系， 为预防阿尔茨海默病的LC细胞丢失以及行为和认知障碍的新疗法奠定基础。

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.