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

美国国家老龄研究所(NIA)宾夕法尼亚州立大学U19“阿尔茨海默病和阿尔茨海默病α-突触核蛋白菌株研究中心 相关痴呆症“。主要调查者：约翰·特罗扬诺夫斯基 中心摘要/摘要：该U19中心在《建议》中追求研究重点 与阿尔茨海默病有关的痴呆症会议“。13它特别侧重于 阿尔茨海默病(AD)和相关痴呆(ADRD)在多病因痴呆的主题领域，路易 躯体(LBD)痴呆(LBD)，包括伴LBS的痴呆症(DLB)和无PD的帕金森氏病 痴呆(PDD)，关于AD14-17生物学定义的新指南，并反映了来自 NIA最近召开的关于“神经退行性疾病的遗传性：当前科学和建议”的会议 用于未来研究“(Frosch M等人，2018年在准备中)。在ADRD中，AD伴丰富的LB共同病理 是AD最常见的亚型。我们假设病理性aSyn的积累导致神经元 不同病理性aSyn株错误折叠和传递形成LBS所致的功能障碍和死亡 和LNS以及aSyn和AD病理相互作用以改变彼此的分布并促成 行为障碍。为实现这些目标，项目一和项目二相辅相成，项目三 和IV通过试图阐明AD aSyn/LBD与PD的aSyn菌株，多系统 萎缩症(MSA)被作为对照研究，因为它的特征是a Syn胶质细胞质包涵体(GCIS) 由一种独特的aSyn菌株组成，该菌株比LBD或AD aSyn病理性菌株更有效 ASyn。同时，项目III使用新的单抗分析AD/LBD的局部神经病理 (单抗)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 这是临床AD表型和原发AD病理的对比。这一点得到了项目IV的补充，该项目 测量认知、血液和脑脊液(CSF)生物标记物，包括aSyn以及SNP阵列，以 更好地了解、诊断和处理AD/LBD的各种临床表现，以促进 朝着护理和疾病管理的精准医学方法迈进。ASyn的里程碑式发现 LBD致病基因(SNCA)改变及病理性aSyn是LBD的致病蛋白 除了aSyn毒株的细胞间传播外，共核病还将aSyn置于 了解AD、aSyn和LBD的发病机制。宾夕法尼亚大学U19中心在四个方面解决了这些关键问题 四核支持的项目。此外，该中心还将与NIA合作，提供生物液、DNA/RNA、 除aSyn外，还收集了过去20年宾夕法尼亚大学ADRD患者的尸检组织和数据 向合格的调查人员提供压力。通过解决不同的aSyn菌株是基础的假设 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 宾夕法尼亚大学U19中心与NIA合作的药物发现和生物标记物开发目标 程序。

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.