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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' 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' 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

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-突触核蛋白内体加工中的作用 痴呆症是路易体病 (LBD) 最有害且代价最高的方面之一，该疾病包括 帕金森病 (PD) 和路易体痴呆 (DLB) 与以下疾病有一些共同的临床特征 尤其是阿尔茨海默病，痴呆症和精神病往往是早期的侵袭性症状。 DLB 患者的病理学特征是错误折叠形式的聚集。 蛋白质 α-突触核蛋白 (aSyn)，称为路易体，在 除了路易体之外，LBD 患者还经常出现淀粉样斑块。 和阿尔茨海默病标志性的神经原纤维缠结以及阿尔茨海默病患者 除了斑块和缠结之外，通常还具有路易体 aSyn 变成的确切机制。 错误折叠以及为何 DLB 中认知能力下降加速尚不清楚。基因研究表明两者之间存在密切联系。 DLB 风险增加与编码载脂蛋白 E（另一种蛋白质）的基因 APOE4 变体之间 我们报道了表达 APOE4 版本的小鼠，这也是阿尔茨海默病风险的核心。 与其他 APOE 基因型相比，人类 APOE 基因加速了 aSyn 聚集和早期死亡。 这一发现与人类 APOE 基因型在小鼠模型中表达时观察到的效果相似 我们的初步数据表明星形胶质细胞和小胶质细胞吸收 aSyn 聚集体。 并通过内溶酶体途径处理它们，这可能作为一种补偿机制 我们建议检查 aSyn 聚集体的细胞生物转运。 通过星形胶质细胞和小胶质细胞的内溶酶体途径，并确定这方面是否存在差异 与 APOE 基因型相关的贩运我们勇敢地承认 APOE4 基因型会损害内溶酶体。 星形胶质细胞和小胶质细胞中 aSyn 聚集体的降解，以及星形胶质细胞中 APOE4 的表达 我们将测试特定的驱动器加速异步病理学，导致大脑功能障碍和神经退行性变。 这种效应的发生是否主要是由于星形胶质细胞或小胶质细胞本身的细胞自主变化， 包括与这些细胞中基因表达的变化有关，或者是否是通过分泌介导的 载脂蛋白 E 蛋白颗粒已知通过与神经元和神经元上的受体结合而产生作用 这些实验的主要目的是阐明 APOE 基因型如何调节内溶酶体加工。 aSyn 在星形胶质细胞和小胶质细胞中的作用，以及如何利用这些知识来开发新的治疗方法 DLB、阿尔茨海默病和其他相关痴呆症。