JPND The locus coeruleus: at the crossroad of dementia syndromes

蓝斑（LC）是一个涉及重要脑功能的脑区，包括注意、记忆和清醒。它包含神经元（神经细胞），使用去甲肾上腺素（去甲肾上腺素）作为传递器，连接到大脑的其他区域。这些疾病通常受到脑部疾病的影响，导致神经元丧失，如阿尔茨海默病、唐氏综合症和帕金森病。LC神经元的丧失可能是这些疾病症状相似的基础。我们的研究小组发现，唐氏综合症（由于多了21号染色体）和其他痴呆症的早期痴呆标志物可能与LC细胞丢失有关。在先前工作的基础上，我们项目的目标是揭示由唐氏综合症、帕金森病和阿尔茨海默病引起的痴呆引起的LC细胞损失的共同机制和途径。我们将使用最先进的技术来(i)探索死后脑材料LC、患者干细胞以及这些疾病的小鼠模型中的细胞退化和细胞功能改变（ii）通过血液和脊髓液生物标志物以及PET脑扫描研究更好地了解痴呆症患者和非痴呆症患者的去甲肾上腺素系统。（iii）分析21号染色体上的特定基因在阿尔茨海默病、帕金森病和唐氏综合症中的作用，并探索它们作为痴呆的共同风险或保护机制的作用。这项工作将更好地了解与LC变性相关的生物标志物，以及它们与其他痴呆生物标志物和患者群体中痴呆状态的关系。这将有助于提高临床诊断，并提供关于痴呆症进展的生物标志物的重要信息，这将对预后和未来的临床研究有价值。这项工作还将提高对患者群体中细胞退化的共同原因和途径的认识，这可能有助于确定新的治疗策略。

The locus coeruleus (LC) is a brain area involved in important brain functions, including attention, memory, and wakefulness. It contains neurons (nerve cells) that use noradrenaline (Norepinephrine) as transmitter that are connected to other brain areas. These are often affected by brain diseases that result in neuronal loss, such as Alzheimer's disease, Down syndrome and Parkinson's disease. Loss of LC neurons may underlie similarities in symptoms between these diseases. Our consortium have found that early markers of dementia in Down syndrome (which is due to an extra chromosome 21) and in other dementias may relate to LC cell loss. Building on previous work, the goal of our project is now to uncover the common mechanisms and pathways associated with LC cell loss that is caused by dementias due to Down syndrome, Parkinson's disease, and Alzheimer's disease. We will use state-of-the-art technologies to (i) explore cell degeneration and cell function alterations in the LC of post-mortem brain material, stem cells derived from patients, and in mouse models of these diseases (ii) Better understand the noradrenaline system in patients with and without dementia using blood and spinal fluid biomarkers and PET brain scan studies, and relate this to established biomarkers (iii) analyze the involvement of specific genes on chromosome 21 in Alzheimer's disease, Parkinson's disease, and Down syndrome and explore their role as common risk or protective mechanisms for dementia. The work will provide better knowledge of biomarkers related to LC degeneration, and their relationship to other dementia biomarkers and to dementia status across patient groups. This will help to improve clinical diagnosis, and also provide important information on biomarkers of dementia progression that will be valuable for prognosis and future clinical studies. The work will also provide improved knowledge of common causes and pathways of cell degeneration across patient groups, which could help to identify new treatment strategies.