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 在发病年龄、神经病理和疾病进展速度方面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患上 广告仍然不被理解。我们最近发现，患有快速发展的阿尔茨海默氏症的人 (RPAD)的淀粉样斑块蛋白质组与典型的散发性AD患者有显著不同。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和 可能影响AD进展速度的因素。自那以后，我们产生了初步数据， 提示类似的斑块蛋白质组学差异也存在于AD患者的另一亚组中 易患AD；载脂蛋白E4携带者。载脂蛋白E4和载脂蛋白E3携带者斑块蛋白质组的比较 在RPAD中改变最多的斑块蛋白中发现了相似的蛋白质差异，以及类似的 载脂蛋白E4携带者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 假设载脂蛋白E4携带者将具有显著改变的淀粉样斑块和蛋白质组 脑淀粉样血管病(CAA)与载脂蛋白E3和载脂蛋白2携带者的比较。我们期待着 ApoE4携带者的蛋白质组学差异将类似于在RPAD中观察到的差异。这项研究将确定 特别易患AD的个体在斑块和CAA中存在蛋白质差异； 比较载脂蛋白E4、载脂蛋白E3和载脂蛋白2表达的蛋白质差异。重要的是，我们会 临床前AD全谱APOE2、3和4携带者蛋白质组组成的测定 正常、轻度认知障碍和晚期阿尔茨海默病。该数据将用作比较人体数据集 对于项目1和2中提出的啮齿动物蛋白质组研究。我们将识别和验证 是AD潜在的新治疗靶点和生物标志物。这个 具体目标是： 1)分析载脂蛋白E4、载脂蛋白E3和载脂蛋白2携带者在斑块蛋白质组中的差异 临床前认知功能正常、轻度认知障碍和晚期AD患者。 2)比较apoE4、apoE3在脑淀粉样血管病变蛋白质组中的差异。 ApoE_2携带者在临床前认知正常、脑梗塞和晚期AD患者S中。 3)验证新的淀粉样蛋白相关蛋白在AD神经病理损害中的积聚 并确定这些蛋白在推动AD病理发展中的作用。