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.

项目概要 阿尔茨海默病 (AD) 是最常见的神经退行性疾病，影响超过 50 全球有数百万人，年龄和遗传变异可能使个人面临高风险。 患有 AD，但具有较高病理风险的独特人群会抵抗并且不会发展 最近的报告表明类淋巴系统和淀粉体（CA）与该病有关。 清除大脑废物，淀粉体积聚细胞碎片，例如蛋白质和 将它们挤出到脑脊液中，在那里它们到达颈部淋巴结并被吞噬。 CA 的正常功能可能在 AD 抵抗中发挥作用，并且可能受到年龄的影响， 了解大脑对有毒蛋白质的先天反应。 聚合对于更深入地了解 AD 病理学的发展至关重要 在这里，我们研究了 CA 是否有助于确定潜在的疾病生物标志物。 通过量化 AD 后海马中 CA 的位置和数量来抵抗 AD 病理学 为了评估抵抗的机制，我们的目标是 回答以下问题： 1) CA 清除细胞内 pTau 是否与以下因素相关： 2) 在出现 AD 相关 tau 病理的个体中，CA、 遗传学和血管病理学影响 tau 积累的密度和分布 回答这些问题将识别并量化新的贡献 该奖学金项目提案提供了在存在高风险的情况下抵抗 AD 的能力。 计算神经科学和遗传流行病学培训的机会。