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: 10428584
• 负责人: Beatrix Magdalena Ueberheide
• 金额: $ 43.06万
• 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/10428584
• 关键词: Address; 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; Gene Proteins; 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; insight; interest; mild cognitive impairment; mouse model; neuropathology; new therapeutic target; novel; novel strategies; novel therapeutics; pre-clinical; sulfated glycoprotein 2; tau Proteins; 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 在发病时代，神经病理学和疾病进展的年龄中有很大程度的异质性 阿尔茨海默氏病（AD）患者。为什么有些患者特别容易受到发展的影响 广告尚未理解。我们最近表明，患有快速进步的阿尔茨海默氏病的人 （RPAD）与典型零星AD的淀粉样蛋白斑块蛋白质组有明显不同。这些牌匾 AD亚型之间的蛋白质差异提供了对有助于牙菌斑发展和的因素的见解 可能影响AD进展率的因素。从那以后，我们生成了初步数据 表明AD患者的另一个亚组也存在类似的斑块蛋白质组学差异 容易受到广告的影响； APOE4载体。 APOE4和APOE3载体中斑块蛋白质组的比较 鉴定出类似的斑块蛋白质蛋白差异，在RPAD中最为改变，并且类似地 APOE4载体中与斑块相关的星形胶质细胞蛋白的水平降低。在这个项目中，我们将测试 假设APOE4载体将具有淀粉样斑块的蛋白质组明显改变，并且 与APOE3和APOE2载体相比，脑淀粉样血管病（CAA）。我们期望这一点 APOE4载体的蛋白质组学差异将与RPAD中观察到的蛋白质组学差异相似。这项研究将确定 斑块和CAA中存在蛋白质差异，特别容易受到AD的影响；具体来说 比较APOE4，APOE3和APOE2表达产生的蛋白质差异。重要的是，我们会的 确定临床前全谱的APOE2、3和4载体的蛋白质组组成 正常，轻度认知障碍和后期广告。这些数据将用作人类比较的数据集 对于项目1和2提出的啮齿动物蛋白质组学研究。我们将确定并验证蛋白质差异 特别有意义，代表了AD的潜在新型治疗靶标和生物标志物。这 具体目的是： 1）表征APOE4，APOE3和APOE2载体之间斑块蛋白质组的差异 临床前的认知应形，MCI和AD晚期病例。 2）表征APOE4，APOE3之间脑淀粉样蛋白血管病蛋白质组的差异 临床前认知正常，M CI和AD AD病例的APOE2载体。 3）验证AD神经病变病变中新型淀粉样相关蛋白的积累 并确定这些蛋白质在推动AD病理发展中的作用。