Upregulated Norepinephrine Synthesis Capacity in Aging

衰老过程中去甲肾上腺素合成能力上调

• 批准号: 10447225
• 负责人: Anne Shively Berry
• 金额: $ 138.63万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447225
• 关键词: Acceleration; Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Animal Model; Anti-Inflammatory Agents; Arousal; Attention; Autopsy; Blood; Blood - brain barrier anatomy; Brain; Brain Stem; Cell Density; Cell Nucleus; Cells; Cerebrospinal Fluid; Chemicals; Cognition; Cognitive; Data; Development; Disease; Disease Progression; Disease Resistance; Dopamine; Early Intervention; Elderly; Enzymes; Financial compensation; Hippocampus (Brain); Human; Impaired cognition; Individual; Individual Differences; Investigation; Lesion; Link; Magnetic Resonance Imaging; Maintenance; Measures; Medial; Mediating; Memory; Memory Loss; Metabolism; Nerve Degeneration; Neuromodulator; Neurons; Norepinephrine; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Performance; Persons; Plasma; Play; Positron-Emission Tomography; Process; Reporting; Research; Resistance; Rodent; Role; Sleep; Source; Standardization; Structure; Targeted Research; Temporal Lobe; Testing; Tracer; Tyrosine; Up-Regulation; biomarker development; cognitive function; combat; entorhinal cortex; financial incentive; healthy aging; hyperphosphorylated tau; imaging biomarker; imaging modality; in vivo; insight; interest; locus ceruleus structure; memory encoding; mild cognitive impairment; mouse model; multimodality; neurobiological mechanism; neurochemistry; neuroregulation; norepinephrine system; novel; prevent; resilience; resistance mechanism; response; tau Proteins; tau aggregation; tau mutation; theories; uptake; ward; young adult

Project summary The locus coeruleus (LC) is a small nucleus in the brainstem that is vulnerable to the accumulation of abnormal tau protein, a neuropathological hallmark of Alzheimer’s disease (AD). The LC is structurally connected to the temporal lobe and may play a role in transmitting abnormal tau through trans-neuronal spread. The LC is the primary producer of the neuromodulator norepinephrine. Norepinephrine is essential for normal attention and memory function. Beyond a role in cognition, norepinephrine serves a myriad of neuroprotective roles which include inhibition of oxidative stress, maintenance of the blood brain barrier, and anti-inflammatory processes. The occurrence of hyperphosphorylated tau in the LC has been linked with loss of norepinephrine-producing LC neurons. The targeting and neurodegeneration of LC is particularly insidious due to the combined loss of cognition-enhancing neuromodulation and loss of neuroprotective functions thus paving the way for disease acceleration and propagation. Despite insults to the LC, there is evidence for upregulation of norepinephrine metabolism in healthy aging, mild cognitive impairment, and AD. We propose upregulation of norepinephrine synthesis in the LC cells remaining represents a mechanism of neurochemical compensation that, in some individuals, wards off cognitive decline and protects against disease spread. In healthy older adult humans, we will define relationships between LC structural integrity, and norepinephrine synthesis levels (Aim 1). We will determine the extent to which elevated norepinephrine synthesis confers a benefit to memory performance (Aim 2). Finally, we will test the hypothesis that elevated norepinephrine synthesis is associated with reduced tau accumulation longitudinally (Aim 3). This multimodal study will combine state-of-the-art magnetic resonance imaging (MRI) to measure LC structural integrity, [18F]Fluoro-m-tyrosine positron emission tomography (PET) to measure norepinephrine/dopamine synthesis capacity, [18F]MK-6240 PET to measure tau pathology, and plasma measures of Ab42/40. If successful, this research will provide new understanding of the neurochemical basis of individual differences in disease progression and will launch a novel avenue of investigation into the role of norepinephrine in disease resilience (supporting maintenance of cognitive function despite pathology) and disease resistance (combatting disease spread).

项目摘要 基因座（LC）是脑干中的一个小核，容易受到异常积累的影响 tau蛋白，阿尔茨海默氏病（AD）的神经病理学标志。 LC在结构上连接到 临时叶，可能在通过跨神经元扩散传播异常的tau中发挥作用。 LC是 神经调节剂去甲肾上腺素的主要生产者。去甲肾上腺素对于正常注意和 内存功能。除了认知中的作用之外，去甲肾上腺素还发挥了无数的神经保护作用 包括抑制氧化应激，维持血脑屏障和抗炎过程。 LC中的高磷酸化TAU的发生与去甲肾上腺素产生的损失有关 LC神经元。 LC的靶向和神经退行性因素尤其是由于合并的损失 认知增强神经调节和神经保护功能的丧失，从而为疾病铺平了道路 加速和传播。尽管侮辱了LC，但仍有上调去甲肾上腺素的证据 健康衰老，轻度认知障碍和AD的代谢。我们提出了去甲肾上腺素的上调 LC细胞中的合成代表了一种神经化学补偿机制，在某些中 个人，远离认知能力下降的病房，可以防止疾病传播。在健康的老年人中，我们 将定义LC结构完整性与去甲肾上腺素合成水平之间的关系（AIM 1）。我们将 确定升高的去甲肾上腺素合成的程度为记忆性能带来好处 （目标2）。最后，我们将检验以下假设：升高的去甲肾上腺素合成与减少有关 tau积累纵向（目标3）。这项多模式研究将结合最先进的磁性 共振成像（MRI）测量LC结构完整性，[18F]氟-m-酪氨酸极性发射 层析成像（PET）测量去甲肾上腺素/多巴胺合成能力，[18F] MK-6240 PET测量 tau病理学和血浆测量AB42/40。如果成功，这项研究将提供新的理解 疾病进展中个体差异的神经化学基础，并将推出新的途径 调查去甲肾上腺素在疾病弹性中的作用（支持维持认知功能 任务病理学）和抗病性（打击疾病扩散）。