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Behavioral and Molecular Consequences of Tau Pathology in Locus Coeruleus in Prodromal Alzheimer's Disease

阿尔茨海默病前驱期蓝斑 Tau 蛋白病理学的行为和分子后果

基本信息

批准号：
10604890
负责人：
ANURADHA KORUKONDA
金额：
$ 4.77万
依托单位：
EMORY UNIVERSITY
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：
2023-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604890
关键词：
Ablation Adrenergic Receptor Affect Affinity Chromatography Agitation Alzheimer&apos s Disease Alzheimer&apos s disease patient American Animal Model Anxiety Arousal Attention Axonal Transport Behavior Behavior assessment Behavioral Brain Brain Stem Caregivers Cell Nucleus Cells Clinical Trials Design Cognitive Cognitive deficits Coupled DSP 4 Dementia Deposition Development Disease Disease Progression Early Diagnosis Emotional Exhibits Family Foundations Frontotemporal Dementia Functional disorder Gene Expression Genes Genetic Gliosis Goals Healthcare Systems Human Hyperactivity Immunohistochemistry Impaired cognition In Situ Hybridization Individual Learning Mediating Memory Memory impairment Mental Depression Modeling Molecular Molecular Profiling Mus Nerve Degeneration Neurobehavioral Manifestations Neurodegenerative Disorders Neurofibrillary Tangles Neurons Neurotoxins Norepinephrine Oxidative Stress Pathogenesis Pathologic Pathology Patients Pattern Phase Phenotype Physiological Processes Prosencephalon Quality of life Ribosomes Senile Plaques Signal Transduction Sleep Sleep Wake Cycle Sleep disturbances Specificity Stress Suggestion Symptoms Synaptic plasticity Techniques Technology Testing Therapeutic Therapeutic Intervention Time Transcript Transgenes Transgenic Mice Translating United States Viral Vector Work aging population anxiety-like behavior astrogliosis behavioral phenotyping beta amyloid pathology cell type common symptom diagnostic tool experience extracellular family burden hyperphosphorylated tau locus ceruleus structure memory consolidation mouse model mutant nerve supply neuroinflammation neuropathology neuropsychiatric symptom neuropsychiatry noradrenergic norepinephrine system postsynaptic preventive intervention prodromal Alzheimer&apos s disease promoter receptor density response socioeconomics targeted treatment tau Proteins tau aggregation tau mutation therapeutic development therapeutic target therapeutically effective transcriptome transcriptome sequencing transcriptomics transmission process

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is the most prevalent form of dementia, affecting 55 million worldwide, and is typified by extracellular deposits of amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Numerous clinical trials designed to alleviate cognitive symptoms by targeting Aβ pathology have failed. However, few studies have comprehensively examined the earlier, prodromal stages, which are characterized by anxiety, agitation, depression, and sleep-wake disturbances that significantly disrupt quality of life and ability to remain independent. The noradrenergic nucleus locus coeruleus (LC) modulates these physiological processes and is the first region to accumulate hyperphosphorylated ‘pretangle’ tau decades before cognitive deficits and Aβ plaques appear. It is therefore important to establish whether a causal relationship between LC tau pathology and prodromal symptoms exists because it can lead to development of therapeutic interventions that relieve these devastating non-cognitive symptoms and possibly halt disease progression. While catastrophic LC cell body degeneration occurs in late AD, the earlier prodromal phases are characterized by aberrant tau accumulation and reductions in LC innervations to projection regions. Moreover, there are suggestions that surviving LC neurons show compensatory increases in firing accompanied by elevations in forebrain adrenergic receptors, thus promoting noradrenergic hyperactivity that could underlie the prodromal symptoms. Since most animal models fail to recapitulate the pathological prodromal feature of hyperphosphorylated tau in the LC, I will develop a biologically valid mouse model where aberrant forms of tau are exclusively expressed in the LC using viral vector-mediated strategies. In Aim 1, I will determine if LC tau burden disrupts LC-sensitive behaviors relevant to prodromal symptoms and exacerbates neuropathology. In Aim 2, I will interrogate the genetic mechanisms that underlie tau-mediated LC dysregulation and degeneration by using Translating Ribosome Affinity Purification (TRAP) to selectively isolate the LC transcriptome and RNAscope in situ hybridization to assess downstream effects on adrenergic receptor gene expression in LC-projecting regions. I hypothesize that aberrant tau in the LC will cause behavioral abnormalities that are commonly associated with the prodromal phase of AD and disrupt normal noradrenergic transmission. Successful completion of these aims will reveal putative molecular mechanistic factors that underlie prodromal symptoms commonly experienced by AD patients and can yield disease-modifying targets for therapeutic interventions.

项目总结