Role of APOE in endosomal processing of alpha-synuclein

APOE 在 α-突触核蛋白内体加工中的作用

基本信息

批准号：
10739682
负责人：
Albert A Davis
金额：
$ 165.84万
依托单位：
WASHINGTON UNIVERSITY
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：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739682
关键词：
Acceleration Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Apolipoprotein E Astrocytes Autopsy Behavior assessment Binding Biological Biological Assay Body Composition Brain Brain region Candidate Disease Gene Cell Extracts Cell surface Cells Cessation of life Clinical Complex Conditioned Culture Media Cost aspects Cultured Cells Data Dementia Dementia with Lewy Bodies Disease E protein Endosomes Exhibits Extracellular Protein Flow Cytometry Gene Expression Gene Expression Profile Genes Genetic Genetic study Genotype Goals Heparan Sulfate Proteoglycan Human Impaired cognition Impairment Individual Inflammation Inflammatory Intercellular Fluid Knock-in Mouse Knock-out Knowledge Lewy Bodies Lewy Body Disease Lewy body pathology Link Lipoprotein Receptor Measures Mediating Microglia Microscopy Molecular Morbidity - disease rate Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Phagocytosis Physiological Process Proteins Psychoses Reporting Risk Role Senile Plaques Structure Symptoms System TREM2 gene Testing Tissue-Specific Gene Expression Variant alpha synuclein apolipoprotein E-3 apolipoprotein E-4 brain cell brain dysfunction brain tissue candidate validation cell type dementia risk experimental study genetic risk factor genetic variant glial activation in vivo mouse model new therapeutic target novel particle pleiotropism prevent receptor risk variant societal costs synucleinopathy trafficking transcriptome sequencing uptake

Acceleration Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Apolipoprotein E Astrocytes Autopsy Behavior assessment Binding Biological Biological Assay Body Composition Brain Brain region Candidate Disease Gene Cell Extracts Cell surface Cells Cessation of life Clinical Complex Conditioned Culture Media Cost aspects Cultured Cells Data Dementia Dementia with Lewy Bodies Disease E protein Endosomes Exhibits Extracellular Protein Flow Cytometry Gene Expression Gene Expression Profile Genes Genetic Genetic study Genotype Goals Heparan Sulfate Proteoglycan Human Impaired cognition Impairment Individual Inflammation Inflammatory Intercellular Fluid Knock-in Mouse Knock-out Knowledge Lewy Bodies Lewy Body Disease Lewy body pathology Link Lipoprotein Receptor Measures Mediating Microglia Microscopy Molecular Morbidity - disease rate Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Phagocytosis Physiological Process Proteins Psychoses Reporting Risk Role Senile Plaques Structure Symptoms System TREM2 gene Testing Tissue-Specific Gene Expression Variant alpha synuclein apolipoprotein E-3 apolipoprotein E-4 brain cell brain dysfunction brain tissue candidate validation cell type dementia risk experimental study genetic risk factor genetic variant glial activation in vivo mouse model new therapeutic target novel particle pleiotropism prevent receptor risk variant societal costs synucleinopathy trafficking transcriptome sequencing uptake

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项目摘要

Role of APOE in endosomal processing of alpha-synuclein Dementia is among the most harmful and costly aspects of Lewy body disease (LBD) which is comprised of Parkinson disease (PD) and dementia with Lewy bodies (DLB) and shares some clinical features with Alzheimer’s disease. In particular, dementia and psychosis are often early and aggressive symptoms in patients with DLB. Pathologically, these illnesses share the feature of aggregation of misfolded forms of the protein alpha-synuclein (aSyn), termed Lewy bodies, which spread throughout multiple brain regions during the disease and are toxic to cells. In addition to Lewy bodies, patients with LBD often have amyloid plaques and neurofibrillary tangles which are hallmarks of Alzheimer’s disease, and patients with Alzheimer’s disease often have Lewy bodies in addition to plaques and tangles. The exact mechanism of how aSyn becomes misfolded and why cognitive decline is accelerated in DLB is unclear. Genetic studies point to a strong link between increased DLB risk and the APOE4 variant of the gene that encodes apolipoprotein E, another protein that is also central to Alzheimer’s disease risk. We reported that mice expressing the APOE4 version of the human APOE gene had accelerated aSyn aggregation and early death compared to other APOE genotypes. This finding is similar to the effects observed when human APOE genotypes are expressed in mouse models of Alzheimer’s disease. Our preliminary data indicate that astrocytes and microglia take up aSyn aggregates and process them through the endolysosomal pathway, which may serve as a compensatory mechanism to degrade harmful aSyn aggregates. We propose to examine the cell biological transit of aSyn aggregates through the endolysosomal pathway in astrocytes and microglia and determine if there are differences in this trafficking related to APOE genotype. We hypothesize that the APOE4 genotype impairs endolysosomal degradation of aSyn aggregates in both astrocytes and microglia, and that astrocyte expression of APOE4 in particular drives accelerated aSyn pathology leading to brain dysfunction and neurodegeneration. We will test whether this effect occurs mainly due to cell-autonomous changes within astrocytes or microglia themselves, including related to changes in gene expression in those cells, or whether it is mediated through secreted apolipoprotein E protein particles that are known to have effects by binding to receptors on both neurons and glia. The main goal of these experiments is to clarify how APOE genotype regulates endolysosomal processing of aSyn in astrocytes and microglia and how this knowledge can be leveraged to develop novel treatments for DLB, Alzheimer’s disease, and other related dementias.

APOE在α-核蛋白内体加工中的作用痴呆症是路易疾病（LBD）最有害和昂贵的方面之一帕金森氏病（PD）和痴呆症具有路易尸体（DLB），并与一些临床特征与阿尔茨海默氏病。特别是，痴呆和精神病通常是早期和侵略性的症状 DLB患者。从病理上讲，这些疾病具有综合形式的聚集的特征蛋白质α-核蛋白（ASYN）称为路易体，它们在多个大脑区域遍布多个大脑区域该疾病对细胞有毒。除路易尸体外，LBD患者经常有淀粉样蛋白斑块和神经原纤维缠结，这是阿尔茨海默氏病的标志，患有阿尔茨海默氏病的患者除了斑块和缠结外，通常还有路易的身体。 Asyn的确切机制尚不清楚DLB中的认知能力下降而置于错误的折叠术以及为什么认知能力下降。遗传学研究指向牢固的联系在编码载脂蛋白E的基因的DLB风险增加与APOE4变体之间，另一种蛋白这也是阿尔茨海默氏病风险的核心。我们报告说表达APOE4版本的小鼠的与其他APOE基因型相比，人ApoE基因已经加速了ASYN聚集和早期死亡。该发现类似于在小鼠模型中表达人APOE基因型时观察到的效果阿尔茨海默氏病。我们的初步数据表明星形胶质细胞和小胶质细胞占Asyn聚集体并通过内溶血途径进行处理，该途径可以作为补偿机制降解有害的Asyn聚集体。我们建议检查ASYN聚集体的细胞生物传输通过星形胶质细胞和小胶质细胞中的内溶性途径，确定这是否存在差异与APOE基因型有关的运输。我们假设APOE4基因型会损害内溶性星形胶质细胞和小胶质细胞中ASYN聚集体的降解，以及ApoE4的星形胶质细胞表达特定驱动会加速ASYN病理学，导致脑功能障碍和神经退行性。我们将测试这种影响是否主要是由于星形胶质细胞或小胶质细胞本身内的细胞自治变化，包括与这些细胞中基因表达的变化有关的，或是否通过分泌介导载脂蛋白E蛋白质颗粒，已知通过与神经元和神经元的受体结合而具有作用神经胶质。这些实验的主要目的是阐明APOE基因型如何调节内溶性处理 Asyn的星形胶质细胞和小胶质细胞以及如何利用这些知识来开发新的治疗方法 DLB，阿尔茨海默氏病和其他相关痴呆症。