Impact of APOE Christchurch mutation on amyloid burden and tau pathology

APOE 基督城突变对淀粉样蛋白负荷和 tau 病理学的影响

基本信息

批准号：
10288471
负责人：
YOUNGHYE MOON
金额：
$ 15.85万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288471
关键词：
Abeta clearance Affect Affinity Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Animal Model Apolipoprotein E Apolipoproteins Astrocytes Binding Binding Sites Biochemical Biochemistry Biological Brain Case Study Cell Surface Receptors Cholesterol Cognitive Complex Data Deposition Development Disease Disease Progression Electrophysiology (science)Exhibits Gene Delivery Gene Expression Gene Mutation Genetic Genetic Polymorphism Genotype Goals Homeostasis Human Immunohistochemistry Impaired cognition Knock-in Mouse Ligands Link Lipid Binding Lipids Lipoprotein Receptor Long-Term Potentiation Measurement Measures Methods Mus Mutation Neonatal Nerve Degeneration Pathogenesis Pathology Plague Play Protein Isoforms Public Health Research Role Senile Plaques Surface Symptoms Synapses Testing Toxic effect Transgenic Mice Variant Virus abeta accumulation abeta deposition apolipoprotein E-3 behavior test beta amyloid pathology cognitive function conditioned fear experimental study extracellular familial Alzheimer disease genetic risk factor hyperphosphorylated tau interest knockin animal lipid metabolism mouse model mutant mutation carrier neuron loss protective factors rare variant receptor receptor binding tau Proteins tau aggregation transcriptome transcriptome sequencing β-amyloid burden

项目摘要

Project Summary/Abstract Apolipoprotein E (APOE), a major apolipoprotein in the brain, transfers cholesterol and lipids through cell surface receptors and maintains lipid homeostasis. APOE polymorphism is also linked to the genetic risk factor for Alzheimer’s disease (AD). For decades, APOE2 has been considered the most protective APOE isoform among the major 3 APOE isoforms, whereas APOE4 accelerates AD pathologies in both human and mouse animal models. In addition, the recent case report has shown that APOE3 Christchurch mutation, a rare APOE variant, could be a beneficial genetic modifier against AD progression. However, the exact function of the APOE Christchurch mutation and its role in AD pathologies are not clearly understood. It has been well studied that APOE isoforms have differential effects on amyloid-β (Aβ) pathology and the lipidated status of APOE has been involved in Aβ deposition. In addition to Aβ pathology, the recent study suggested APOE isoform modulates tau pathology and tau-related neurodegeneration. In this proposal, we pursue to investigate the roles of APOE Christchurch mutation in AD pathologies. We hypothesized that APOE Christchurch mutation provides beneficial effects against AD progression by modulating lipidation of APOE. APOE Christchurch mutation could impact both Aβ plaque burden and tau-related pathology. The goal of this proposal to determine how APOE Christchurch mutation interact to suppress the pathologies caused by Aβ and Tau.

项目摘要/摘要载脂蛋白E（APOE），大脑中主要的载脂蛋白，将胆固醇和脂质通过细胞表面转移受体并保持脂质稳态。阿尔茨海默氏病（AD）数十年来，APOE2被认为是最保护性的APOE同工型主要的3个APOE同工型，而APOE4在人和小鼠动物中加速了AD病理此外，最近的案例报告表明，APOE3 Christchurch突变是一种罕见的APOE变体可能是针对AD进展的有益的遗传修饰符。基督城突变，在AD病理中的作用尚不清楚。已经很好地研究了APOE同工型对淀粉样蛋白β（Aβ）病理具有差异作用除Aβ病理外，APOE的脂化状态还参与了Aβ沉积。建议的APOE同工型模块化是TAU病理学和与TAU相关的神经变性追求研究Apoe Christchurch突变在AD病理学中的作用。克赖斯特彻奇突变通过调节APOE的脂肪来对AD的进展产生有益的影响。 Apoe Christchurch突变可能会影响Aβ斑块负担和与TAU相关的病理。提议确定Apoe Christchurch突变如何相互作用以抑制由 aβ和tau。