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.

项目总结