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Exploring Blood-Brain Barrier Dysfunction in Alzheimer's Disease

探索阿尔茨海默病中的血脑屏障功能障碍

基本信息

批准号：
10242177
负责人：
ERIC V SHUSTA
金额：
$ 38.04万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242177
关键词：
Address Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Apolipoprotein E Astrocytes Automobile Driving Behavioral Blood Blood - brain barrier anatomy Blood Vessels Brain Brain region CRISPR/Cas technology Cell Communication Cell Culture System Cell Differentiation process Cell Line Cells Cerebellum Chronic Clock protein Data Dementia Disease Disease Progression Disorientation Endothelial Cells Endothelium Environment Extracellular Fluid Extravasation Functional disorder Generations Genes Genetic Genotype Global Change Hippocampus (Brain)Human Human Genetics Inflammatory Response Ions Laboratories Language Mediating Memory Loss Metabolic Metabolism Methods Modeling Molecular Moods Movement Nature Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Neurons Pathogenesis Patients Pericytes Permeability Play Process Property Proteins Proteome Proteomics Risk Factors Role Sampling Secondary to Senile Plaques Severities Signal Transduction Somatic Cell Source Supporting Cell System Techniques Temporal Lobe Therapeutic Intervention Tissues Transport Process apolipoprotein E-3 apolipoprotein E-4 blood-brain barrier function brain endothelial cell brain tissue cell type comparative differential expression extracellular genome editing human disease human model immune function induced pluripotent stem cell induced pluripotent stem cell technology innovation insight nervous system disorder neuron loss neurovascular unit novel programs protective allele relating to nervous system restoration sex stem cell model tool

项目摘要

ABSTRACT Alzheimer’s disease (AD) is a debilitating neurological disease and the leading cause of dementia. The pathophysiology of AD includes neuronal loss and is characterized by the buildup of amyloid plaques and neurofibrillary tangles, leading to extensive study of these disease processes. Recently, evidence has suggested that blood-brain barrier (BBB) dysfunction may contribute to the progression and severity of AD. However, the mechanisms of BBB dysfunction in AD remain to be elucidated. The BBB acts as a signaling and transport interface between the blood and brain, and with its very low permeability and a wealth of molecular transport systems, the BBB helps regulate the extracellular fluid of the brain. While brain endothelial cells mediate these BBB functions, the BBB is greatly influenced by endothelial cell interactions with supporting cells of the neurovascular unit (NVU), including astrocytes, pericytes and neurons. Currently, it is unclear which human BBB functions are affected in AD, what causes these BBB changes, and which NVU cell types are responsible. BBB dysfunction in AD could be caused by genetic factors such as ApoE allele, a major AD risk factor, or may be secondary to neurodegenerative disease processes. In this proposal, we will investigate both possibilities. First, by deploying a powerful and innovative approach for modeling human disease using induced pluripotent stem cell (iPSC) technology, we will investigate the impact of ApoE allele on BBB function. We have recently demonstrated that it is possible to derive each of the key NVU cell types from patient- sourced iPSCs, and that these models can be used to better understand BBB dysfunction in genetic human disease. Here, the iPSC-derived NVU model will be used to investigate ApoE allele combinations to determine their effects on BBB barrier, transport and immune functions and to identify the key NVU cell type driving the observed effects. Next, to investigate the possibility that BBB dysfunction is secondary to disease processes, we will identify the molecular changes in human AD brain endothelial cells and then examine their function in the iPSC-derived NVU model. Brain endothelial cells will be isolated from brain tissue of AD patients and state- of-the-art multiplex proteomic methods used to identify proteins that are differentially abundant in AD brain endothelium. We will then use gene editing techniques to create iPSC lines in which we can modulate expression of the differentially regulated genes and evaluate their effects on BBB function using the multicellular iPSC-derived NVU model. A better understanding of the sources and forms of BBB dysfunction in AD will yield new mechanistic insights into AD disease progression, and suggest new avenues for therapeutic intervention.