The role of APOE and Bone Morphogenic protein 4 (BMP4) in early cellular pathophysiology of Alzheimer's Disease

APOE 和骨形态发生蛋白 4 (BMP4) 在阿尔茨海默病早期细胞病理生理学中的作用

基本信息

批准号：
10535543
负责人：
Anne Kathryn Linden
金额：
$ 4.68万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10535543
关键词：
Address Age Age of Onset Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Apolipoprotein E Astrocytes Binding Biochemical Biological Biological Assay Brain CRISPR/Cas technology Calcium Calcium Oscillations Cell Death Cell Line Cell physiology Cells Clinical Coculture Techniques Cognition Cognitive Cognitive deficits Dementia Development Diagnosis Disease Disease Progression E protein Functional disorder Gene Expression Gene Frequency Genes Genetic Transcription Genotype Glutamates Goals Human Impaired cognition Individual Induced pluripotent stem cell derived neurons Inherited Intraventricular Infusion Ionomycin Laboratories Learning Link Lipids Longevity Memory Methods Microglia Modeling Molecular Profiling Morphology Mus Neurites Neurodegenerative Disorders Neurons Pathogenesis Pathogenicity Pathologic Pathology Patients Phenotype Phosphorylation Physiology Population Predisposition Presynaptic Terminals Process Protein Isoforms Protein Secretion Proteins Regulation Research Risk Risk Factors Rodent Role Series Signal Transduction Synapses Testing Time Tissue-Specific Gene Expression Transcript Variant Work age related aged aging brain apolipoprotein E-3 apolipoprotein E-4 base bone morphogenic protein brain cell cell type cellular pathology cognitive process cytokine differentiation protocol disease-causing mutation endoplasmic reticulum stress genetic risk factor induced pluripotent stem cell inhibitor lipidomics mouse model neuron loss neurotrophic factor p38 Mitogen Activated Protein Kinase plasmonics premature preservation protein expression release factor response sensor single cell sequencing spatial memory stressor successful intervention tau Proteins tau-1 transcriptome transcriptomics uptake virtual

Address Age Age of Onset Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Apolipoprotein E Astrocytes Binding Biochemical Biological Biological Assay Brain CRISPR/Cas technology Calcium Calcium Oscillations Cell Death Cell Line Cell physiology Cells Clinical Coculture Techniques Cognition Cognitive Cognitive deficits Dementia Development Diagnosis Disease Disease Progression E protein Functional disorder Gene Expression Gene Frequency Genes Genetic Transcription Genotype Glutamates Goals Human Impaired cognition Individual Induced pluripotent stem cell derived neurons Inherited Intraventricular Infusion Ionomycin Laboratories Learning Link Lipids Longevity Memory Methods Microglia Modeling Molecular Profiling Morphology Mus Neurites Neurodegenerative Disorders Neurons Pathogenesis Pathogenicity Pathologic Pathology Patients Phenotype Phosphorylation Physiology Population Predisposition Presynaptic Terminals Process Protein Isoforms Protein Secretion Proteins Regulation Research Risk Risk Factors Rodent Role Series Signal Transduction Synapses Testing Time Tissue-Specific Gene Expression Transcript Variant Work age related aged aging brain apolipoprotein E-3 apolipoprotein E-4 base bone morphogenic protein brain cell cell type cellular pathology cognitive process cytokine differentiation protocol disease-causing mutation endoplasmic reticulum stress genetic risk factor induced pluripotent stem cell inhibitor lipidomics mouse model neuron loss neurotrophic factor p38 Mitogen Activated Protein Kinase plasmonics premature preservation protein expression release factor response sensor single cell sequencing spatial memory stressor successful intervention tau Proteins tau-1 transcriptome transcriptomics uptake virtual

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项目摘要

Project Summary Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disorder categorized clinically by premature deficits in learning and memory that gradually progress to severe dementia. Although familial forms of the disease are caused by mutations in specific genes, the majority of AD occurs sporadically (sAD). The strongest risk factor for sAD diagnosis is age, implicating biochemical changes that occur across lifespan that increase pathogenic susceptibility. One of the changes that occur throughout aging in both human and rodent brains is an increase in BMP4 signaling, in a manner that is significantly negatively correlated with cognitive decline and decreased spatial memory in mouse models. The strongest genetic risk factor for sporadic Alzheimer’s disease is apolipoprotein E (APOE) genotype; the APOEε4 isoform is significantly more prevalent in AD populations and has been linked to increased disease progression and earlier age of onset. Previous work in the Kessler lab has shown that APOEε4 neurons, compared to APOEε3 isogenic control neurons, express increased levels of phosphorylated tau and have greater predisposition to cell death in response to external stressors such as ionomycin. The current proposal seeks to understand the interaction between increased BMP4 and APOEε4 expression at the cellular level to understand early sAD disease pathogenesis. To answer this question, our laboratory has generated induced pluripotent stem cells (iPSCs) from patients with sporadic AD and used CRISPR-/Cas9 editing of APOEε3/4 cells to create isogenic APOEε3/3 lines. These cells are then differentiated into neurons and astrocytes to determine cell-autonomous and non-cell autonomous cellular pathology involved in increased BMP4 signaling and APOEε4 expression. The first aim will test the hypothesis that increased BMP4 in tandem with APOEε4 expression elicit additive effects that negatively alters astrocytic expression and homeostatic functions. To test this hypothesis, transcriptomics will be used to determine differential gene expression and subsequent studies will be used to address protein expression and functional changes may occur. The second aim will utilize iPSC patient-derived cocultures of neurons and astrocytes in matched or mismatched isogenic pairs to determine non-cell autonomous changes that occur as a result of increased BMP4 signaling and APOEε4 genotype, testing the hypothesis that APOEε4 astrocytes, along with increased BMP4 signaling, exaggerate pathological cascades in neurons, leading to decreased viability subsequent cell death of neurons. The purpose of the first aim is to determine how astrocytes, whose trophic support is necessary for neuronal viability, alter homeostatic functions in response to sAD risk factors. The second aim will uncover how these cell-autonomous changes in astrocytes ultimately modify early disease pathology in neurons. The overall long-term goal is to identify early targetable mechanisms for successful intervention in this devastating disease.

项目摘要阿尔茨海默氏病（AD）是一种异质性神经退行性疾病，临床上按过早分类学习和记忆的缺陷，逐渐发展为严重的痴呆症。虽然家族形式的疾病是由特定基因突变引起的，大多数AD偶发地发生（SAD）。坚强 SAD诊断的危险因素是年龄，在寿命中发生的隐含生化变化会增加致病性易感性。人类和啮齿动物大脑中整个衰老的变化之一是 BMP4信号传导的增加，与认知能力下降显着相关的方式和鼠标模型中的空间内存减少。零星阿尔茨海默氏病的强大遗传危险因素是载脂蛋白E（APOE）基因型； APOEε4同工型在AD种群中明显更为普遍，并且 HA与疾病进展的增加和发病年龄有关。凯斯勒实验室的先前工作表明APOEε4神经元与APOEε3等源性对照神经元相比表达增加的水平磷酸化的tau，对外部压力源（例如离子霉素。当前的提案旨在了解增加BMP4和APOEε4之间的相互作用在细胞水平上表达以了解早期的Sad疾病发病机理。为了回答这个问题，我们实验室已经从零星AD患者中产生了诱导的多能干细胞（IPSC），并使用 APOEε3/4细胞的CRISPR-/CAS9编辑创建异基因APOEε3/3线。然后将这些细胞分化进入神经元和星形胶质细胞，以确定涉及的细胞自主和非细胞自主细胞病理在增加的BMP4信号传导和APOEε4表达中。第一个目标将检验BMP4增加的假设与ApoEε4表达同时引起的添加效应，从而改变星形胶质细胞表达和稳态功能。为了检验该假设，转录组学将用于确定差异基因表达和随后的研究将用于解决蛋白质表达，功能变化可能第二个目标将利用IPSC患者衍生的神经元和星形胶质细胞的共培养不匹配的等源性对确定BMP4增加的非细胞自主变化信号传导和APOEε4基因型，检验了APOEε4星形胶质细胞的假设以及BMP4的增加信号传导，夸张的神经元病理级联反应，导致生存力降低随后的细胞死亡神经元。第一个目的的目的是确定星形胶质细胞的营养支持是如何进行的神经元的生存力，会改变稳态功能，以应对悲伤的危险因素。第二个目标将发现如何这些细胞自主变化的星形胶质细胞最终改变了神经元的早期疾病病理。总体长期目标是确定在这种毁灭性疾病中成功干预的早期目标机制。