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)S的神经病理特征是淀粉样β蛋白(Aβ)和tau的积聚 蛋白质。到目前为止，治疗努力主要集中在Aβ上，并显示出有限的成功，强调 需要其他干预方法，特别是那些能够针对与 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的影响：到40岁时，80%的人在LC中出现tau聚集，到50岁时，50%的人出现tau聚集。 的个体在内嗅皮层(EC)表现出tau聚集，提示tau从LC进展到 内侧颞叶(MTL)。然而，tau的传播机制尚不清楚。累计 来自动物研究的证据表明，病理性tau通过轴突和细胞间的传递进行传播。 而突触和神经元的活动水平促进了这一过程。此外，最近的一项研究使用了一只老鼠 LC神经元的椒角tau模型和光遗传刺激提示，新奇时相LC 激活可以防止与椒盐牛排相关的有害变化。相比之下，与压力相关的补药 激活LC使LC神经元健康恶化，并促进与tau相关的抑郁行为 在EC中的积累。我们自己的初步数据显示，与新颖性相关的较低LC激活与 在认知健康的老年人中，EC中更高的tau沉积和更陡峭的记忆力下降。这 证据构成了假设的科学前提，即时相与紧张性静息状态的LC活动可能 与tau的传播机制相关，并最终预测认知能力下降。这项提案的目标是 是为了研究在静息状态下检测到的时相和紧张性LC活动之间的平衡关系- 状态fMRI数据和tau在EC和MTL中的沉积，跨越AD连续和认知的所有阶段 拒绝。为了实现这一点，我们将解决两个方法学障碍：(2)计算血液动力学 在静息状态功能磁共振成像中使用最优定义的区域和特定对象的反卷积进行模糊 血流动力学响应函数，以及(Ii)使用新的事件检测技术来检测 去卷曲LC的时相和紧张性活动。我们量化各阶段之间的平衡的方法 通过同时使用LC BOLD-fMRI、纤维光度法 钙成像，以及在静息实验条件下从清醒的啮齿动物收集的瞳孔扩张数据。 将这些最先进的新方法与tau-，Aβ-PET和来自 哈佛衰老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 目的：1)研究LC活动横断面模式与年龄的关系， 不同生物标记物水平的个体中的性别、tau和β-淀粉样蛋白病理，目的2)与LC相关 认知功能衰退的激活模式是AD病理的一种功能。这些目标共同促进了我们的 理解初始tau传播的机制基础及其与认知的相关性。