Neuronal Vulnerability to Lipid Droplets and Cholesterol in Alzheimer's Disease
阿尔茨海默病中神经元对脂滴和胆固醇的脆弱性
基本信息
- 批准号:10644533
- 负责人:
- 金额:$ 69.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-15 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAffectAgeAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease patientAlzheimer&aposs disease riskAlzheimer’s disease biomarkerAmericanAmyloid beta-ProteinAstrocytesBiological AssayBiologyBrain DiseasesCell CommunicationCell Differentiation processCell LineCell NucleusCell ProliferationCell SurvivalCell modelCellsCellular AssayCerebrumCholesterolCholesterol EstersCholesterol HomeostasisChromatinClinicalClustered Regularly Interspaced Short Palindromic RepeatsCoculture TechniquesDataDementiaDemyelinationsDiseaseDisease ProgressionFatty AcidsGenesGeneticGenetic RiskGenetic TranscriptionGoalsHomeostasisHumanImageImpairmentIndividualInduced pluripotent stem cell derived neuronsLesionLipidsMediatingMicrogliaModelingMolecularNerve DegenerationNeurodegenerative DisordersNeuronal DysfunctionNeuronsNonesterified Fatty AcidsOligodendrogliaOrganoidsOutcomePatientsPhenotypePlasmaProteinsRNAResearchRoleSmall Nuclear RNAStressSynapsesToxic effectTriglyceridesaging brainaging populationapolipoprotein E-4brain healthcell typeclinical phenotypeclinically relevantcohortdementia riskeffective therapyepigenomicsexcitatory neurongenome wide association studygenome-wide analysisinduced pluripotent stem celllipid metabolismmultiple omicsmyelinationnerve stem cellneuralneuroprotectionneuropsychiatrynormal agingoligodendrocyte precursorpolygenic risk scorereceptorremyelinationrepairedrisk varianttau Proteinstranscriptomicstriacsin C
项目摘要
ABSTRACT
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that afflicts over 6.5 million Americans.
Despite decades of research on amyloid-β (Aβ) and Tau lesions, effective treatment remains out of reach.
Mounting AD genome-wide association studies (GWAS) risk loci provide opportunities for understanding
disease biology and developing effective treatment. Multiple AD GWAS risk genes, such as APOE, are pivotal
for lipid metabolism that is essential to brain health and disease. Under stress or in the aging brain, both
astrocytes and microglia show abnormal lipid metabolism and accumulation of lipid droplets (LD). Although
glial LD are known to be largely neuroprotective, LD formation in human neurons and its cellular and molecular
ramifications are less clear. With excitatory neurons (Ex) derived from human induced pluripotent stem cells
(iPSC), we have shown that APOE4 Ex neurons co-cultured with astrocytes accumulated more LD than
APOE2/3 neurons. Our single-cell transcriptomic analysis of AD brain also identified an impaired neuron-
oligodendrocyte precursor cell (OPC) communication mediated by APOE and its receptor LDLR. Interestingly,
neural cholesterol was recently found to be essential to OPC proliferation and remyelination. We thus
hypothesize that abnormal neuronal LD and cholesterol in AD contribute to neuronal damage and impaired
neuron remyelination. Leveraging our expertise on using iPSC-derived neurons and cortical organoids as
cellular models for brain disorders, we will characterize the cell type vulnerability to LD/cholesterol and the
corresponding epigenomic/transcriptomic changes in the context of AD risk alleles. In Aim 1, to determine the
neural vulnerability to LD and its clinical relevance in AD, we will co-culture Ex and Inhibitory (Inh) neurons of a
cohort of 60 patient-specific iPSC lines, and assay neural LD, free fatty acids, cholesterol, and neural
morphometrics, which will then be associated with APOE alleles and non-APOE AD polygenic risk scores.
These cellular phenotypes will also be correlated with patients’ longitudinal plasma lipid levels and other
clinical outcomes. In Aim 2, to understand molecular mechanisms underlying neural vulnerability to LD, we will
perform single-cell RNA/ATAC-sequencing on the same neural co-cultures used in Aim 1 to identify genes with
chromatin accessibility and transcription correlated with cellular LD in each cell type. In Aim 3, to examine the
effect of AD risk alleles on cholesterol-mediated neuron-OPC communication and myelination, we will first use
CRISPR editing to generate isogenic iPSC lines carrying AD risk alleles and then differentiate them into
myelinating cerebral organoids. We will examine the effects of AD risk alleles on neuronal cholesterol levels as
well as the OPC proliferation and neuron myelination. This study will significantly advance our understanding of
the cellular and molecular mechanisms of neuronal vulnerability to abnormal LD and cholesterol in AD.
抽象的
阿尔茨海默病 (AD) 是一种毁灭性的神经退行性疾病,影响着超过 650 万美国人。
尽管对β淀粉样蛋白(Aβ)和Tau蛋白损伤进行了数十年的研究,但有效的治疗仍然遥不可及。
开展 AD 全基因组关联研究 (GWAS) 风险位点为理解提供了机会
疾病发展生物学和有效治疗至关重要。
对于大脑健康和疾病至关重要的脂质代谢,无论是在压力下还是在老化的大脑中。
星形胶质细胞和小胶质细胞表现出异常的脂质代谢和脂滴(LD)的积累。
胶质LD 已知在很大程度上具有神经保护作用,人类神经元及其细胞和分子中的LD 形成
对于源自人类诱导多能干细胞的兴奋性神经元 (Ex) 的影响尚不清楚。
(iPSC),我们发现与星形胶质细胞共培养的 APOE4 Ex 神经元积累了比星形胶质细胞更多的 LD
我们对 AD 大脑的 APOE2/3 神经元的单细胞转录组分析也发现了受损的神经元。
APOE 及其受体 LDLR 介导少突胶质细胞前体细胞 (OPC) 通讯。
最近发现神经胆固醇对于 OPC 增殖和髓鞘再生至关重要。
AD中异常的神经元LD和胆固醇会导致神经元损伤和受损
利用我们在使用 iPSC 衍生的神经元和皮质类器官方面的专业知识。
脑部疾病的细胞模型,我们将描述细胞类型对 LD/胆固醇的脆弱性和
在目标 1 中,确定 AD 风险等位基因中相应的表观基因组/转录组变化。
神经元对 LD 的脆弱性及其在 AD 中的临床相关性,我们将共培养一个神经元的 Ex 和抑制 (Inh) 神经元
60 个患者特异性 iPSC 系的队列,并测定神经 LD、游离酸脂肪、胆固醇和神经
然后将其与 APOE 等位基因和非 APOE AD 多基因风险评分相关联。
这些细胞表型也将与患者的纵向血浆脂质水平和其他相关
在目标 2 中,为了了解 LD 神经脆弱性的分子机制,我们将
对目标 1 中使用的相同神经共培养物进行单细胞 RNA/ATAC 测序,以识别具有
在目标 3 中,染色质可及性和转录与每种细胞类型的细胞 LD 相关。
AD 风险等位基因对胆固醇介导的神经元-OPC 通讯和髓鞘形成的影响,我们将首先使用
CRISPR 编辑生成携带 AD 风险等位基因的同基因 iPSC 系,然后将其分化为
我们将检查 AD 风险等位基因对神经元胆固醇水平的影响。
这项研究将显着增进我们对 OPC 增殖和神经元髓鞘形成的理解。
AD 中神经对异常 LD 和胆固醇脆弱性的细胞和分子机制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Jubao Duan其他文献
Jubao Duan的其他文献
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{{ truncateString('Jubao Duan', 18)}}的其他基金
Assay and Data Generation Center (ADGC) for the Model of iPSC-derived Neurons for NPD (MiNND)
用于 NPD (MiNND) iPSC 衍生神经元模型的测定和数据生成中心 (ADGC)
- 批准号:
10653338 - 财政年份:2023
- 资助金额:
$ 69.14万 - 项目类别:
Modeling Alzheimer's disease genetic variants in hiPSC
在 hiPSC 中模拟阿尔茨海默病遗传变异
- 批准号:
10594510 - 财政年份:2019
- 资助金额:
$ 69.14万 - 项目类别:
Modeling Alzheimer's disease genetic variants in hiPSC
在 hiPSC 中模拟阿尔茨海默病遗传变异
- 批准号:
10374953 - 财政年份:2019
- 资助金额:
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Modeling Alzheimer's disease genetic variants in hiPSC
在 hiPSC 中模拟阿尔茨海默病遗传变异
- 批准号:
9923537 - 财政年份:2019
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Systematic Functional Interpretation of Regulatory Variants in Neuropsychiatric Disorders
神经精神疾病调节变异的系统功能解释
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10549349 - 财政年份:2016
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神经精神疾病调节变异的系统功能解释
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10381609 - 财政年份:2016
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