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: 10629346
• 负责人: Anne Shively Berry
• 金额: $ 134.04万
• 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/10629346
• 关键词: Acceleration; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amygdaloid structure; Amyloid; Animal Model; Anti-Inflammatory Agents; Arousal; Attention; Autopsy; Binding; Blood; Blood - brain barrier anatomy; Brain; Brain Stem; Cell Density; Cell Nucleus; Cells; Cerebrospinal Fluid; Chemicals; Child; Cognition; Cognitive; Compensation; Data; Development; Disease; Disease Progression; Disease Resistance; Dopamine; Early Intervention; Elderly; Enzymes; Hippocampus; Human; Impaired cognition; Individual; Individual Differences; Investigation; Lesion; Link; Magnetic Resonance Imaging; Maintenance; Measures; Medial; Mediating; Memory; Memory Loss; Memory impairment; Metabolism; Methods; Nerve Degeneration; Neuromodulator; Neurons; Norepinephrine; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Performance; Persons; Plasma; Positron-Emission Tomography; Process; Reporting; Research; Resistance; Rodent Model; Role; Source; Standardization; Structure; Targeted Research; Temporal Lobe; Testing; Tracer; Tyrosine; Up-Regulation; biomarker development; cognitive function; combat; entorhinal cortex; financial incentive; healthy aging; human old age (65+); hyperphosphorylated tau; imaging biomarker; in vivo; insight; interest; locus ceruleus structure; memory encoding; mild cognitive impairment; mouse model; multimodality; neurobiological mechanism; neurochemistry; neuropathology; neuroprotection; neuroregulation; norepinephrine system; novel; prevent; resilience; resistance mechanism; response; sleep regulation; tau Proteins; tau aggregation; tau mutation; theories; transmission process; 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 蓝斑（LC）是脑干中的一个小核团，容易受到异常的 tau蛋白是阿尔茨海默病（AD）的神经病理学标志。LC在结构上连接到 并且可能在通过跨神经元扩散传递异常tau蛋白中起作用。LC是 神经调节剂去甲肾上腺素的主要生产者。去甲肾上腺素对正常的注意力至关重要， 记忆功能除了在认知中的作用，去甲肾上腺素还具有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中过度磷酸化tau蛋白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变是特别阴险的，由于组合的损失， 认知增强的神经调节和神经保护功能的丧失，从而为疾病铺平道路 加速和传播。尽管对LC有损伤，但有证据表明去甲肾上腺素 在健康老龄化、轻度认知障碍和AD中的代谢。我们建议上调去甲肾上腺素 在LC细胞中剩余的合成代表了神经化学补偿的机制，在某些情况下， 个体，避免认知能力下降，防止疾病传播。在健康的老年人中，我们 将定义LC结构完整性和去甲肾上腺素合成水平之间的关系（目标1）。我们将 确定去甲肾上腺素合成增加对记忆表现的益处 (Aim 2）的情况。最后，我们将检验去甲肾上腺素合成增加与减少有关的假设。 tau纵向积累（Aim 3）。这项多模态研究将结合联合收割机最先进的磁 共振成像（MRI）测量LC结构完整性，[18 F]氟-间-酪氨酸正电子发射 断层扫描（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Ab 42/40的血浆测量。如果成功，这项研究将提供新的认识， 疾病进展中个体差异的神经化学基础，并将推出一种新的途径， 去甲肾上腺素在疾病恢复中的作用（支持认知功能的维持） 尽管病理学）和抗病性（对抗疾病传播）。