Evaluating Mechanisms Underlying Resistance in Alzheimer’s Disease

评估阿尔茨海默氏病耐药机制

• 批准号: 10605519
• 负责人: Julian Dieter Dallmeier
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-19 至 2026-04-18
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605519
• 关键词: Adult; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Autopsy; Biological; Biological Markers; Blood Vessels; Brain; Cells; Cellular Structures; Cerebrospinal Fluid; Cervical lymph node group; Clinical; Code; Computer Models; Computer software; Corpora amylacea; Data; Dementia; Development; Disease; Disease Resistance; Elderly; Exhibits; Fellowship; Functional disorder; Genetic; Genetic Risk; Genetic Variation; Genomics; Goals; Heterozygote; Hippocampus; Image; Impaired cognition; Individual; Knowledge; Linear Regressions; Liquid substance; Location; Methods; Modeling; Neocortex; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathologic; Pathology; Pathway interactions; Persons; Play; Prevention; Proteins; Protocols documentation; Reporting; Reproducibility; Resistance; Risk; Risk Factors; Risk Reduction; Role; Sample Size; Sampling; Senile Plaques; Source Code; Standardization; Structure; System; Tauopathies; Testing; Therapeutic Intervention; Tissue Donors; Training; Travel; United States; Variant; Waste Products; apolipoprotein E-4; brain pathway; brain tissue; cohort; comorbidity; computational neuroscience; density; dentate gyrus; experimental group; extracellular; genetic epidemiology; genetic risk factor; genetic variant; genome sequencing; glymphatic system; high risk; hyperphosphorylated tau; interdisciplinary approach; mind control; neocortical; neuropathology; neuroprotection; novel; open source; protein aggregation; repository; resistance mechanism; response; tau Proteins; tau aggregation; variant detection; wasting; whole genome; β-amyloid burden

PROJECT SUMMARY Alzheimer disease (AD) is the most prevalent neurodegenerative disorder, affecting over 50 million people worldwide. Age and genetic variation can place individuals at high risk for developing AD, yet a unique subset of people at higher risk resist pathology and do not develop disease. Recent reports implicate the glymphatic system and corpora amylacea (CA) in the clearance of brain waste products. Corpora Amylacea amass cellular debris such as proteins and extrude them into the CSF where they travel to the cervical lymph nodes and are phagocytosed. The proper functioning of CA may play a role in AD resistance, and might be influenced by age, degree of pathology, and genetic risk. Understanding the brain’s innate response to toxic protein aggregates is essential for a deeper understanding of the development of AD pathology and potentially identifying disease biomarkers. Here we investigate whether CA contribute to resistance to AD pathology by quantifying CA location and number in the hippocampus of post- mortem AD and control brains. To evaluate the mechanisms underlying resistance we aim the answer the following questions: 1) Is clearance of intracellular pTau by CA associated with resistance to AD pathology? 2) In individuals who develop AD-related tau pathology, do CA, genetics, and vascular pathology influence the density of tau accumulation and the distribution across the hippocampus? Answering these questions will identify and quantify novel contributions to resistance of AD in the presence of elevated risk. This fellowship project proposal offers the opportunity to train in computational neuroscience and genetic epidemiology.

项目摘要 阿尔茨海默氏病（AD）是最普遍的神经退行性疾病，影响了50多个 全球百万人。年龄和遗传变异可以使个人处于高风险 开发广告，但具有较高风险抗性病理的独特子集，并且不发展 疾病。最近的报告暗示了糖基体系和链氨酰酰亚胺（CA） 清除脑废品。 Corpora amylacea amylacea Amass细胞碎片，例如蛋白质和 将它们挤入CSF中，然后进入宫颈淋巴结并被吞噬。 CA的正确功能可能在AD抗性中起作用，并且可能受年龄的影响， 病理程度和遗传风险。了解大脑对有毒蛋白的天生反应 聚集体对于更深入地了解AD病理的发展至关重要 潜在地识别疾病生物标志物。在这里，我们调查CA是否有助于 通过量化CA的位置和海马中的数量来抵抗AD病理学 Mortem广告和控制大脑。为了评估抗药性的机制，我们针对 回答以下问题：1）与CA相关的细胞内PTAU清除 对广告病理的抵抗？ 2）在发展与广告相关的tau病理学的个体中，做CA， 遗传学和血管病理影响TAU积累的密度和分布 穿过海马？回答这些问题将确定并量化新颖的贡献 在风险升高的情况下，AD的抵抗力。这个奖学金项目提案提供了 培训计算神经科学和遗传流行病学的机会。