Center On Alpha-synuclein Strains In Alzheimer Disease & Related Dementias

阿尔茨海默病α-突触核蛋白菌株研究中心

• 批准号: 10452557
• 负责人: VIRGINIA M LEE
• 金额: $ 362.24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452557
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Archives; Area; Autopsy; Bioinformatics; Biological; Biological Markers; Biological Models; Biometry; Blood; Caring; Cells; Cessation of life; Clinical; Cognition; Cognitive; Collaborations; Complement; Cytoplasmic Inclusion; DNA; Data; Dementia; Dementia with Lewy Bodies; Diagnosis; Disease; Disease Management; Functional disorder; Genetic Markers; Goals; Guidelines; Heterogeneity; Image; Impaired cognition; In Vitro; Lead; Lewy Bodies; Lewy Body Dementia; Lewy neurites; Link; Measures; Mediating; Molecular; Monoclonal Antibodies; Multiple System Atrophy; National Institute on Aging; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurons; Parkinson Disease; Parkinson' s Dementia; Pathogenicity; Pathologic; Pathology; Patients; Pennsylvania; Preparation; Principal Investigator; Proteins; RNA; Recommendation; Research Personnel; Research Priority; SNP array; Science; Technology; Tissues; Universities; Vision; Work; alpha synuclein; alpha synuclein gene; behavioral impairment; biomarker development; data management; design; disease heterogeneity; disease phenotype; drug discovery; in vivo; medical schools; meetings; mixed dementia; neuropathology; new therapeutic target; novel; novel therapeutics; precision medicine; programs; progressive neurodegeneration; symposium; synucleinopathy; targeted biomarker; transmission process

National Institute on Aging (NIA) Penn U19 “Center On Alpha-synuclein Strains In Alzheimer Disease & Related Dementias”. Principal Investigator: John Q. Trojanowski Center Summary/Abstract: This U19 Center pursues research priorities in the “Recommendations of the Alzheimer's disease-related dementias conference”.13 It especially focuses on priorities that address Alzheimer's disease (AD) and related dementias (ADRD) in topic areas of multiple etiology dementias, Lewy body (LB) dementias (LBD), including dementia with LBs (DLB) and Parkinson's disease without (PD) and with dementia (PDD), new guidelines on the biological definition of AD14-17 and reflects recommendations from a recent NIA meeting on “Neurodegenerative Disease Transmissibility: Current Science and Recommendations for Future Research” (Frosch M et al, in preparation, 2018). Among ADRD, AD with abundant LB co-pathology is the most common subtype of AD. We hypothesize that accumulations of pathological aSyn lead to neuron dysfunction and death due to misfolding and transmission of different strains of pathological aSyn to form LBs and LNs and that aSyn and AD pathology interact to modify the distribution of each other and contribute to behavioral impairments. To accomplish these goals, Projects I and II complement each other and Projects III and IV by seeking to elucidate aSyn strains underlying AD+aSyn/LBD compared to PD, Multiple system atrophy (MSA) is studied as a control because it is characterized by aSyn glial cytoplasmic inclusions (GCIs) that are comprised of a distinct aSyn strain which is more potent than LBD or AD+aSyn strains of pathological aSyn. In parallel, Project III analyzes regional AD/LBD neuropathology with novel monoclonal antibodies (mAbs) to correlate these data with diverse cognitive difficulties and structural imaging. A 2X2 design is used that contrasts clinical AD phenotypes and primary AD pathologies. This is complemented by Project IV which measures cognition, blood and cerebrospinal (CSF) biomarkers, including aSyn, as well as SNP arrays, to better understand, diagnose and manage diverse clinical manifestations of AD/LBD in order to advance towards a precision medicine approach for care and disease management. The landmark discoveries of aSyn gene (SNCA) alterations pathogenic for LBD and that pathological aSyn is the disease protein in synucleinopathies, in addition to the cell-to-cell spread of aSyn strains, places aSyn at center stage for understanding mechanisms of AD+aSyn and LBD. This Penn U19 Center addresses these key issues in four Projects supported by four Cores. Moreover, this Center also will work with NIA to provide biofluids, DNA/RNA, autopsy tissue and data collected from ADRD patients over the past 20 years at Penn in addition to aSyn strains to qualified investigators. By addressing the hypothesis that distinct aSyn strains underlie AD+aSyn/LBD, we will clarify the molecular basis of heterogeneity in AD+aSyn/LBD while opening up new targets for drug discovery and biomarker development in at the Penn U19 Center in collaboration with NIA program.

国家老龄化研究所（NIA）宾夕法尼亚大学19“中心α-突触核蛋白菌株在阿尔茨海默病和 相关的痴呆症”。主要研究者：John Q.特罗亚诺夫斯基 中心摘要/摘要：U19中心在“世界大学推荐”中追求研究优先权。 阿尔茨海默病相关痴呆症会议”。 阿尔茨海默病（AD）和相关痴呆（ADRD）在多病因痴呆领域的主题，Lewy 身体（LB）痴呆（LBD），包括具有LB的痴呆（DLB）和无帕金森病（PD）和 痴呆症（PDD），关于AD 14 -17生物学定义的新指南，并反映了 最近NIA会议上“神经退行性疾病的传播：当前的科学和建议 未来研究”（Frosch M等人，准备中，2018）。在ADRD中，AD与丰富的LB共病 是AD最常见的亚型。我们假设病理性aSyn的积累导致神经元 由于不同菌株的病理性aSyn的错误折叠和传播而形成LB， 以及aSyn和AD病理学相互作用以改变彼此的分布并有助于 行为障碍为实现这些目标，项目一和项目二相辅相成， 和IV通过寻求阐明与PD相比AD+aSyn/LBD潜在的aSyn菌株，多系统 萎缩（MSA）作为对照进行研究，因为其特征在于aSyn胶质细胞胞质内含物（GCI） 由不同的aSyn菌株组成，其比LBD或AD+aSyn菌株更有效地引起病理性 aSyn。同时，项目III用新型单克隆抗体分析了局部AD/LBD神经病理学 （mAbs）来将这些数据与不同的认知困难和结构成像相关联。采用2X2设计 对比临床AD表型和原发性AD病理。项目四补充了这一点， 测量认知，血液和脑脊液（CSF）生物标志物，包括aSyn，以及SNP阵列， 更好地了解，诊断和管理AD/LBD的各种临床表现，以促进 为护理和疾病管理提供精确的医疗方法。aSyn的里程碑式发现 基因（SNCA）改变对LBD致病，并且病理性aSyn是LBD中的疾病蛋白。 除了aSyn菌株的细胞间传播之外，突触核蛋白病还将aSyn置于 了解AD+aSyn和LBD的机制。这个宾夕法尼亚大学U19中心解决这些关键问题，在四个 由四个核心支持的项目。此外，该中心还将与NIA合作，提供生物流体，DNA/RNA， 除了aSyn之外，还收集了过去20年在Penn从ADRD患者中收集的尸检组织和数据 向合格的研究人员提供。通过解决不同的aSyn菌株 AD+aSyn/LBD，我们将阐明AD+aSyn/LBD异质性的分子基础，同时开辟新的 药物发现和生物标志物开发的目标，在宾夕法尼亚大学U19中心与NIA合作 程序.