JPND The locus coeruleus: at the crossroad of dementia syndromes

蓝斑(LC)是一个大脑区域，参与重要的大脑功能，包括注意力、记忆力和觉醒。它包含使用去甲肾上腺素(去甲肾上腺素)作为递质的神经元(神经细胞)，这些神经元连接到大脑的其他区域。这些人通常会受到导致神经元丧失的脑部疾病的影响，如阿尔茨海默病、唐氏综合症和帕金森氏症。LC神经元的丢失可能是这些疾病症状相似的原因。我们的研究小组发现，唐氏综合症(由于额外的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。在以前工作的基础上，我们项目的目标是揭示与唐氏综合症、帕金森病和阿尔茨海默病引起的痴呆有关的LC细胞损失的常见机制和途径。我们将使用最先进的技术来(I)探索死后脑材料、来自患者的干细胞以及这些疾病的小鼠模型中的细胞变性和细胞功能变化(Ii)利用血液和脊髓液生物标记物以及PET脑扫描研究更好地了解患有痴呆症和非痴呆症患者的去甲肾上腺素系统，并将其与已建立的生物标志物相关联(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征中的参与，并探讨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退变相关的生物标记物，以及它们与其他痴呆症生物标记物的关系，以及患者组中的痴呆症状态。这将有助于提高临床诊断水平，也将为痴呆进展的生物标志物提供重要信息，对预后和未来的临床研究具有重要价值。这项工作还将提供关于患者群体中细胞退化的常见原因和途径的更好知识，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.