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.

摘要 阿尔茨海默病（AD）的神经病理学标志是β淀粉样蛋白（Aβ）和tau蛋白的积累。 proteins.到目前为止，治疗工作主要集中在Aβ上，并显示出有限的成功，强调了 需要采取其他干预办法，特别是那些能够针对与人权有关的机制的办法， 病理学的最初传播。蓝斑（LC）已被确定为最早的区域之一 受tau影响：到40岁时，80%的个体在LC中表现出tau聚集，到50岁时，50%的个体在LC中表现出tau聚集。 的个体在内嗅皮质（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蛋白通过轴突和细胞间传递进行传播， 并且突触和神经元活动水平促进了这一过程。此外，最近的一项研究使用大鼠 LC神经元中的预缠结tau蛋白模型和光遗传学刺激表明， 活化保护免于与预缠结tau相关的有害变化。相反，与压力相关的滋补品 LC激活损害LC神经元健康并促进与tau蛋白相关的抑郁行为 在欧盟积累。我们自己的初步数据表明，较低的新奇相关的LC激活与 EC中较高的tau沉积和认知健康的老年个体中较陡的记忆衰退。这 证据形成了这一假设的科学前提，即阶段性与紧张性静息状态LC活动可能是 与tau蛋白传播机制相关，并最终预测认知能力下降。这项提案的目的是 是检查在静息状态下检测到的阶段性与紧张性LC活性之间的平衡之间的关系， 状态fMRI数据和tau沉积在EC和MTL在AD连续体和认知的所有阶段 下降为了实现这一点，我们将解决两个方法上的障碍：（ii）考虑血流动力学 根据最佳定义的区域和受试者特异性， 血流动力学反应功能，和（ii）使用新的事件检测技术检测的周期， 去卷积LC中的相位和紧张活性。我们的方法用于量化阶段性 将使用同步LC BOLD-fMRI、纤维光度法对与强直性LC活性进行微调和验证 钙成像和瞳孔扩张数据收集从清醒的啮齿动物在休息实验条件。 将这些最先进的新方法与tau-，Aβ-PET和纵向认知数据相结合， 哈佛老化大脑研究和阿尔茨海默病神经成像倡议，将使我们能够检查 以下目的：目的1）调查LC活动的横截面模式与年龄之间的关联， 不同生物标志物水平的个体中的性别、tau蛋白和β-淀粉样蛋白病理学，目的2）将LC 激活模式与认知功能下降的关系。总之，这些目标有助于我们 理解初始tau传播的机制基础及其与认知的相关性。