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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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