Proteomic studies on the role of Apolipoprotein E and other amyloid associated proteins in AD

载脂蛋白 E 和其他淀粉样蛋白相关蛋白在 AD 中作用的蛋白质组学研究

• 批准号: 10621836
• 负责人: Beatrix Magdalena Ueberheide
• 金额: $ 43.57万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621836
• 关键词: Affect; Affinity Chromatography; Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Astrocytes; Automobile Driving; Behavioral; Binding Proteins; Bioinformatics; Biometry; Brain; Cell Culture Techniques; Cerebral Amyloid Angiopathy; Co-Immunoprecipitations; Cognitive; Data; Data Set; Development; Disease; Disease Progression; Future; Genes; Genotype; Heterogeneity; Human; Immunohistochemistry; Impaired cognition; Individual; Lesion; Mass Spectrum Analysis; Microglia; Microvascular Dysfunction; Neurites; Onset of illness; Pathogenesis; Pathway interactions; Patients; Persons; Play; Protein Isoforms; Proteins; Proteome; Proteomics; Risk Factors; Rodent; Role; Senile Plaques; Severities; Signal Pathway; Subgroup; Techniques; Testing; Therapeutic Intervention; Tissues; Transgenic Organisms; Ubiquitin; Validation; Variant; alpha synuclein; apolipoprotein E-3; apolipoprotein E-4; brain tissue; comparative; disorder subtype; human data; insight; interest; mild cognitive impairment; mouse model; neuropathology; new therapeutic target; novel; novel strategies; novel therapeutics; pre-clinical; sulfated glycoprotein 2; tau Proteins; therapeutic biomarker; therapeutic candidate; transcriptomics

PROJECT 1- SUMMARY/ABSTRACT There is a large degree of heterogeneity in the age of onset, neuropathology and rate of disease progression in patients with Alzheimer's disease (AD). Why some patients are particularly vulnerable to the development of AD is still not yet understood. We recently showed that people with rapidly progressive Alzheimer's disease (rpAD) had a significantly different amyloid plaque proteome from those with typical sporadic AD. These plaque protein differences between AD subtypes offered insight into factors that contribute to plaque development and factors that may influence the rate of progression of AD. We have since generated preliminary data that suggests that similar plaque proteomic differences are also present in another subgroup of AD patients vulnerable to AD; apoE4 carriers. The comparison of the plaque proteome in apoE4 and apoE3 carriers identified similar protein differences in plaque proteins that were most altered in rpAD, as well as similarly decreased levels of plaque-associated astrocyte proteins in apoE4 carriers. In this project we will test the hypothesis that apoE4 carriers will have a significantly altered proteome of amyloid plaques and cerebral amyloid angiopathy (CAA) in comparison to apoE3 and apoE2 carriers. We expect that proteomic differences in apoE4 carriers will be similar to those observed in rpAD. This study will identify protein differences present in plaques and CAA in individuals particularly vulnerable to AD; specifically comparing the protein differences that result from apoE4, apoE3 and apoE2 expression. Importantly, we will determine the proteome composition of apoE2, 3 and 4 carriers for the full spectrum of AD from preclinical normal, mild cognitive impairment and late stage AD. This data will be used as a comparative human dataset for rodent proteomic studies proposed in projects 1 and 2. We will identify and validate protein differences that are of particular interest, which represent potential novel therapeutic targets and biomarkers of AD. The specific aims are: 1) Characterize the differences in the plaque proteome between apoE4, apoE3 and apoE2 carriers in preclinical cognitivenormal, MCI and late AD cases. 2) Characterize the differences in the cerebral amyloid angiopathy proteome between apoE4, apoE3 and apoE2 carriers in preclinical cognitive normal, M CI and late AD case s. 3) To validate the accumulation of novel amyloid associated proteins in AD neuropathological lesions and to determine the role of these proteins in driving AD pathology development.

项目 1 - 摘要/摘要 不同人群的发病年龄、神经病理学和疾病进展速度存在很大程度的异质性 阿尔茨海默病（AD）患者。为什么有些患者特别容易出现 AD目前还没有被理解。我们最近表明，患有快速进展的阿尔茨海默病的人 (rpAD) 的淀粉样斑块蛋白质组与典型散发性 AD 患者显着不同。这些牌匾 AD 亚型之间的蛋白质差异有助于深入了解导致斑块形成的因素和 可能影响 AD 进展速度的因素。此后我们生成了初步数据 表明类似的斑块蛋白质组差异也存在于 AD 患者的另一个亚组中 容易患AD； apoE4 携带者。 apoE4和apoE3携带者斑块蛋白质组的比较 在 rpAD 中变化最大的斑块蛋白中发现了类似的蛋白质差异，以及类似的 apoE4 携带者中斑块相关星形胶质细胞蛋白水平降低。在这个项目中我们将测试 假设 apoE4 携带者的淀粉样斑块蛋白质组显着改变， 与apoE3和apoE2携带者相比，脑淀粉样血管病（CAA）。我们期望 apoE4 携带者的蛋白质组差异与 rpAD 中观察到的相似。这项研究将确定 特别容易患 AD 的个体中，斑块和 CAA 中存在蛋白质差异；具体来说 比较 apoE4、apoE3 和 apoE2 表达导致的蛋白质差异。重要的是，我们将 从临床前确定全谱 AD 的 apoE2、3 和 4 载体的蛋白质组组成 正常、轻度认知障碍和晚期 AD。该数据将用作比较人类数据集 用于项目 1 和 2 中提出的啮齿动物蛋白质组学研究。我们将识别并验证蛋白质差异 特别令人感兴趣的是，它们代表了 AD 的潜在新治疗靶点和生物标志物。这 具体目标是： 1) 表征apoE4、apoE3和apoE2携带者之间斑块蛋白质组的差异 临床前认知正常、MCI 和晚期 AD 病例。 2) 表征apoE4、apoE3之间脑淀粉样血管病蛋白质组的差异 临床前认知正常、M CI 和晚期 AD 病例中的 apoE2 携带者。 3) 验证新型淀粉样蛋白相关蛋白在 AD 神经病理病变中的积累 并确定这些蛋白质在驱动 AD 病理发展中的作用。