Contribution of locus coeruleus activity patterns on tau deposition in Alzheimer's disease

蓝斑活性模式对阿尔茨海默病中 tau 蛋白沉积的贡献

• 批准号: 10646691
• 负责人: Prokopis Christou Prokopiou
• 金额: $ 25.05万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646691
• 关键词: Accounting; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Experimentation; Animals; Axon; Behavior; Biological Markers; Brain; Brain Stem; Calcium; Cell Nucleus; Cells; Cessation of life; Clinical; Clinical Trials; Cognition; Cognitive; Data; Deposition; Detection; Disease; Dorsal; Early Diagnosis; Early Intervention; Epidemic; Equilibrium; Event; Exhibits; Face; Fiber; Fire - disasters; Frequencies; Functional Magnetic Resonance Imaging; Goals; Health; Human; Image; Impaired cognition; Individual; Interneurons; Intervention; Lateral; Learning; Link; Longitudinal cohort; Measurement; Measures; Medial; Mediating; Memory; Memory Loss; Methodology; Methods; Mission; Modeling; Mydriasis; Names; Neocortex; Neurofibrillary Tangles; Neurons; Norepinephrine; Pathologic; Pathology; Pattern; Phase; Photometry; Physiological; Pontine structure; Positron-Emission Tomography; Process; Public Health; Rattus; Reporting; Rest; Rodent; Senile Plaques; Signal Transduction; Source; Stereotyping; Stress; Synapses; Temporal Lobe; Testing; Therapeutic; United States; United States National Institutes of Health; Work; abeta accumulation; abeta deposition; age effect; age related; aging brain; animal data; animal imaging; awake; behavior influence; beta amyloid pathology; cognitive performance; coping; depressive behavior; design; detection method; effective therapy; entorhinal cortex; healthy aging; hemodynamics; human imaging; hyperphosphorylated tau; imaging study; improved; in vivo; insight; locus ceruleus structure; neocortical; neuroimaging; neuropathology; novel; optogenetics; response; sex; success; tau Proteins; tau aggregation; temporal measurement; tool; transmission process; β-amyloid burden

ABSTRACT Alzheimer's disease (AD)'s neuropathologic hallmarks are the accumulation of amyloid-beta (Aβ) and tau proteins. Thus far, therapeutic efforts have been mainly focused on Aβ and showed limited success, underscoring the need for alternative approaches of intervention, particularly those that can target mechanisms related to the initial propagation of pathology. The locus coeruleus (LC) has been identified as one of the earliest regions affected by tau: by the age of 40, 80% of individuals exhibit tau aggregation in the LC, and by the age of 50, 50% of individuals exhibit tau aggregation in the entorhinal cortex (EC), suggesting tau progression from the LC to the medial temporal lobe (MTL). However, the mechanism of tau propagation is yet unknown. Accumulated evidence from animal research suggests that pathologic tau propagates via axons and cell-to-cell transmission and that synaptic and neuronal activity levels facilitate this process. Furthermore, a recent study using a rat model of pretangle tau in LC neurons and optogenetic stimulation suggested that novelty-like phasic LC activation protects against the deleterious changes linked to pretangle tau. In contrast, stress-associated tonic LC activation worsens LC neuronal health and promotes depressive behaviors that have been associated with tau accumulation in the EC. Our own preliminary data shows that lower novelty-related LC activation is related to higher tau deposition in the EC and steeper memory decline in cognitively healthy older individuals. This evidence forms the scientific premise for the hypothesis that phasic versus tonic resting-state LC activity may be associated with mechanisms of tau propagation and ultimately predict cognitive decline. The goal of this proposal is to examine the relationship between the balance between phasic versus tonic LC activity detected in resting- state fMRI data and tau deposition in the EC and the MTL across all stages of the AD continuum and cognitive decline. To achieve this, we will resolve two methodological barriers: (ii) accounting for the hemodynamic blurring in resting-state fMRI using deconvolution in terms of an optimally defined region- and subject-specific hemodynamic response function, and (ii) using novel event-detection techniques for the detection of periods of phasic and tonic activity in the deconvoluted LC. Our methodology for quantifying the balance between phasic versus tonic LC activity will be fine-tuned and validated using simultaneous LC BOLD-fMRI, fiber photometry calcium imaging, and pupil dilation data collected from awake rodents during resting-experimental conditions. Combining these state-of-the-art novel methods with tau-, Aβ-PET, and longitudinal cognitive data from the Harvard Aging Brain Study and the Alzheimer Disease Neuroimaging Initiative, will allow us to examine the following aims: Aim 1) To investigate the associations between cross-sectional patterns of LC activity with age, sex, tau, and beta-amyloid pathology among individuals of varying biomarker levels, Aim 2) To relate LC activation patterns to cognitive decline as a function of AD pathology. Together, these aims contribute to our understanding of the mechanistic underpinnings of initial tau propagation and its relevance for cognition.

抽象的 阿尔茨海默氏病 (AD) 的神经病理学标志是β-淀粉样蛋白 (Aβ) 和 tau 蛋白的积累 蛋白质。迄今为止，治疗工作主要集中在 Aβ 上，但取得的成功有限，强调 需要采取替代干预措施，特别是那些可以针对与 病理学的初始传播。蓝斑（LC）已被确定为最早的区域之一 受 tau 蛋白影响：到 40 岁时，80% 的人在 LC 中表现出 tau 蛋白聚集，到 50 岁时，50% 的人在 LC 中出现 tau 蛋白聚集 的个体在内嗅皮层 (EC) 中表现出 tau 聚集，表明 tau 从 LC 进展到 内侧颞叶（MTL）。然而，tau 传播的机制尚不清楚。积累 来自动物研究的证据表明病理性 tau 通过轴突和细胞间传播传播 突触和神经元活动水平促进了这一过程。此外，最近一项使用大鼠的研究 LC 神经元中的 pretangle tau 模型和光遗传学刺激表明新颖的相性 LC 激活可防止与 pretangle tau 相关的有害变化。相反，与压力相关的补品 LC 激活会恶化 LC 神经元健康并促进与 tau 相关的抑郁行为 EC 中的积累。我们自己的初步数据表明，新颖性相关的 LC 激活较低与 认知健康的老年人中，EC 中的 tau 蛋白沉积量较高，记忆力下降较严重。这 证据构成了以下假设的科学前提：阶段性与强直性静息态 LC 活动可能是 与 tau 传播机制相关并最终预测认知能力下降。本提案的目标 是为了检查静息状态下检测到的阶段性 LC 活动与强直性 LC 活动之间的平衡之间的关系 状态 fMRI 数据以及 AD 连续体和认知所有阶段 EC 和 MTL 中的 tau 沉积 衰退。为了实现这一目标，我们将解决两个方法论障碍：（ii）考虑血流动力学 根据最佳定义的区域和受试者特定情况使用反卷积在静息态 fMRI 中进行模糊处理 血流动力学响应函数，以及（ii）使用新颖的事件检测技术来检测周期 解卷积 LC 中的相位和强直活动。我们量化阶段之间平衡的方法 将使用同步 LC BOLD-fMRI、光纤光度测定法对 LC 活性与强直性 LC 活性进行微调和验证 钙成像和在静息实验条件下从清醒啮齿动物收集的瞳孔扩张数据。 将这些最先进的新颖方法与来自 tau-、Aβ-PET 和纵向认知数据相结合 哈佛大脑老化研究和阿尔茨海默病神经影像计划将使我们能够检查 以下目标： 目标 1) 研究 LC 活性横截面模式与年龄之间的关联， 不同生物标志物水平个体之间的性别、tau 蛋白和 β-淀粉样蛋白病理学，目标 2) 将 LC 联系起来 作为 AD 病理学功能的认知衰退的激活模式。这些目标共同有助于我们 了解初始 tau 传播的机制基础及其与认知的相关性。