Role of APOE in endosomal processing of alpha-synuclein

载脂蛋白E在α-突触核蛋白内体加工中的作用 痴呆症是路易体病(LBD)危害最大、代价最高的方面之一，由以下几个方面组成 帕金森病(PD)和路易体痴呆(DLB)，临床特征与 阿尔茨海默氏症。特别是，痴呆症和精神病通常是早期和侵略性的症状。 DLB型患者。在病理学上，这些疾病具有错误折叠的形式聚集的特征 蛋白质α-突触核蛋白(ASyn)，称为路易小体，在 这种疾病对细胞有毒性。除了路易小体外，LBD患者还经常有淀粉样斑块 和神经原纤维缠结，这是阿尔茨海默病的特征，以及阿尔茨海默病患者 除了斑块和缠结外，通常还有路易体。ASyn如何变成 错误折叠，以及为什么DLB的认知能力下降加速，目前尚不清楚。基因研究指出两者之间存在很强的联系 DLB风险增加和编码载脂蛋白E的基因的APOE4变异之间的关系 这也是阿尔茨海默病风险的核心。我们报告说，表达APOE4版本的小鼠 与其他载脂蛋白E基因相比，人载脂蛋白E基因加速了aSyn聚集和早期死亡。 这一发现与人类载脂蛋白E基因在小鼠模型中表达时观察到的效果相似 阿尔茨海默氏症。我们的初步数据表明，星形胶质细胞和小胶质细胞聚集在一起。 并通过内溶酶体途径对它们进行处理，这可能是一种补偿机制 降解有害的aSyn聚集体。我们建议研究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，并确定在这方面是否存在差异 与载脂蛋白E基因有关的贩运。我们假设APOE4基因会损害内溶酶体。 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APOE4的表达 特定的驱动因素加速了aSyn的病理，导致了大脑功能障碍和神经退化。我们将测试 无论这种影响主要是由于星形胶质细胞或小胶质细胞本身的细胞自主性变化所致， 包括与这些细胞中基因表达的变化有关，或者是否通过分泌的 载脂蛋白E蛋白颗粒已知通过与神经元和 神经胶质细胞。这些实验的主要目的是阐明apoE基因如何调节内切酶的加工。 ASyn在星形胶质细胞和小胶质细胞中的表达，以及如何利用这一知识开发新的治疗方法 痴呆症、阿尔茨海默病和其他相关痴呆症。

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.