Project II "aSyn Strains & Diverse Synucleinopathies"

项目二“aSyn菌株

• 批准号: 10020335
• 负责人: JOHN Q. TROJANOWSKI
• 金额: $ 45.66万
• 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/10020335
• 关键词: Alpha-Synuclein transgenic mouse; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Autopsy; Bioinformatics; Biological; Biology; Biometry; Brain; Clinical; Complement; Core Grant; Cytoplasmic Inclusion; Data; Dementia; Deposition; Development; Disease; Follow-Up Studies; Grant; Heterogeneity; Hippocampus (Brain); Human; In Vitro; Injections; Knock-in; Knock-in Mouse; Knock-out; Lewy Bodies; Lewy Body Dementia; Lewy Body Disease; Lewy neurites; Mediating; Modeling; Molecular Conformation; Multiple System Atrophy; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuroglia; Neurons; Parkinson Disease; Pathologic; Pathology; Pennsylvania; Property; Protein Precursors; Research; Research Personnel; Seeds; Senile Plaques; Study Subject; Testing; Tg2576; Transgenic Mice; Universities; Wild Type Mouse; Work; alpha synuclein; cerebral atrophy; comorbidity; data management; improved; in vitro Model; in vivo; innovation; insight; medical schools; mouse model; mouse synuclein alpha; mutant; novel; phenotypic data; protein TDP-43; recruit; synucleinopathy; tau Proteins

PROJECT II: Pathologic Alpha-synuclein Strains & Diverse Synucleinopathies Project II Leader: J.Q. Trojanowski; Co-Investigators: V.M.-Y. Lee & K. Luk Project II Summary/Abstract Project II (formerly Project IV and renumbered II to improve the flow of the research) in this new U19 “Center On Alpha-synuclein Strains In Alzheimer Disease & Related Dementias” at the University of Pennsylvania (Penn) Perelman School of Medicine (PSOM) tests the hypothesis that heterogeneity and progression of alpha-synuclein (aSyn) pathology in Lewy bodies (LBs) and neurites (LNs) of Parkinson's disease without (PD) or with dementia (PDD) and dementia with LBs (DLB), as well as Alzheimer's disease (AD) with aSyn (AD+aSyn) LBs and LNs co-pathologies represent the spread of different neuronal aSyn strains.1 We compare these strains to each other and with aSyn strains from multiple system atrophy (MSA) glial cytoplasmic inclusions (GCI) which rarely appear in AD or in combination with LBs/LNs. This will advance insights into how distinct aSyn strains in AD+aSyn vs PD vs PDD vs DLB vs MSA drive clinical and pathological heterogeneity of these disorders. Since dementia in PDD and DLB, referred to as LB dementia (LBD), frequently is accompanied by AD co-pathologies, including Aβ amyloid plaques and neurofibrillary tau inclusions, and 50% of AD patients have LBs, we also test the hypothesis that aSyn strains in PDD vs DLB vs AD+aSyn brains induce Aβ and tau pathologies whereas aSyn strains in PD vs MSA brains lacking AD pathology might not. Project II collaborates with Project I, which performs in vitro aSyn strain studies and provides Project II with highly characterized and validated aSyn strains from postmortem AD+aSyn, PD, LBD and MSA brains as well as in vitro amplified LB and GCI aSyn strains. For these studies, living subjects are studied in Core B and Projects III/IV and their brains are obtained through Core C while Core D provides data management, biostatistics and bioinformatics support. The extent to which the models of synucleinopathies induced by intracerebral injections of LB and GCI aSyn strains in Project II correspond to authentic human AD+aSyn vs PD vs LBD vs MSA will be assessed. Thus, Project II works closely with all U19 Center Cores/Projects to determine if the LB aSyn strain (aSyn-LB) from PD vs AD+aSyn vs LBD brains compared to the MSA GCI aSyn strain (aSyn-GCI) differentially induce pathological aSyn in neurons versus glia as well as recruit AD-like Aβ and tau deposits or other neurodegenerative disease co-pathologies such as TDP-43. This will be done following intracerebral injections of these aSyn strains into wild type (WT) mice, human WT aSyn transgenic (Tg) mice (line 61) on a mouse aSyn knock out (KO) background (KO61) and CNP-aSyn (M2) Tg mice with an aSyn KO background (KOM2) that model GCIs compared to Tg mouse models of AD-like Aβ plaques (5xFAD, Tg2576, APP knock in mice) and a Tg mouse model of AD-like tau pathologies (PS19 line). The hypothesis tested in Project II emerged from preliminary studies of intracerebral injections of synthetic aSyn preformed fibrils (PFF) into some of these models, and we innovate now by injecting different authentic human brain derived aSyn-LB and aSyn-GCI (including recently developed more potent aSyn-LB strains developed by Project I) into our models to elucidate the basis for distinct aSyn strain mediated clinicopathological heterogeneity in AD+aSyn vs PD vs LBD compared to MSA lacking AD pathology as control. Specifically, we test the novel hypothesis that AD+aSyn, PD, LBD and MSA result from different aSyn strains as well as that aSyn-LB strains from AD+aSyn and LBD brains, but not aSyn-LB strains from PD brains and the aSyn-GCI strains from MSA brains, mediate development of AD co-pathologies.

项目II：病理性α-突触核蛋白菌株和多种突触核病 项目II负责人：J.Q.Trojanowski；联合调查员：V.M.-Y.Lee和K.Luk 项目二摘要/摘要 新的U19中的项目II(原项目IV，重新编号II，以改善研究流程) 阿尔茨海默病和相关痴呆的α-突触核蛋白菌株研究中心 宾夕法尼亚州(宾夕法尼亚州)佩雷尔曼医学院(PSOM)测试了异质性和 帕金森病路易体(LBS)和轴突(LNS)α-突触核蛋白(ASyn)病理研究进展 无痴呆(PD)或痴呆症(PDD)和伴有LBS的痴呆症(DLB)以及阿尔茨海默病 (AD)伴有aSyn(AD+aSyn)的LBS和LNS共同病理代表不同神经元aSyn的扩散 菌株1我们将这些菌株相互比较，并与来自多系统萎缩(MSA)的aSyn菌株进行比较。 胶质细胞胞质包涵体(GCI)，在AD或合并LBS/LNS时很少出现。这将会推动 洞察AD+aSyn与PD、PDD、DLB与MSA中不同的aSyn菌株如何推动临床和 这些疾病的病理异质性。由于PDD和DLB型痴呆，称为LB型痴呆 常伴有AD共病，包括Aβ淀粉样斑块和神经原纤维tau 包涵体，并且50%的AD患者有LBS，我们还检验了PDD中的aSyn株与DLb中的aSyn株与DLb中的aSyn株 AD+aSyn脑导致Aβ和tau病变，而帕金森病患者与无AD的MSA脑中的aSyn菌株 病理学可能不会。项目II与项目I合作，项目I在体外进行aSyn毒株研究，并 为项目II提供来自死后AD+aSyn、PD、LBD的高度特征化和验证的aSyn毒株 MSA脑部以及体外扩增的LB型和GCI型aSyn株。在这些研究中，活的受试者是 在核心B和项目III/IV中研究，他们的大脑是通过核心C获得的，而核心D提供数据 管理、生物统计和生物信息学支持。联核病模型在多大程度上 项目II中的LB型和GCI型aSyn毒株脑内注射诱导的结果与真人一致 将评估AD+aSyn VS PD VS LBD VS MSA。因此，项目II与所有U19中心密切合作 核心/项目以确定PD与AD+aSyn与LBD大脑中的LBaSyn菌株(aSyn-Lb)是否与 MSA GCI aSyn株(aSyn-GCI)在神经元和胶质细胞中不同地诱导病理性aSyn以及 招募AD样TDP和tau沉积或其他神经退行性疾病的共同病理，如β-43。这 将在将这些aSyn毒株注射到野生型(WT)小鼠(人WT aSyn)脑内后进行 在小鼠aSyn基因敲除(KO)背景(KO61)和CNP-aSyn(M2)TG上转基因(TG)小鼠(第61系) 具有ASyn KO背景(KOM2)的小鼠与类AD Aβ的TG小鼠模型GCI的比较 斑块(5xFAD，Tg2576，APP敲打小鼠)和Tg小鼠AD样tau病理模型(PS19行)。 在项目II中检验的假设来自对脑内注射合成药物的初步研究 ASyn在其中一些模型中预制了纤维(PFF)，我们现在通过注入不同的正品进行创新 人脑来源的aSyn-Lb和aSyn-GCI(包括最近开发的更有效的aSyn-Lb菌株 由项目I开发)到我们的模型中，以阐明不同的aSyn菌株介导的基础 AD+aSyn与PD与LBD的临床病理异质性与缺乏AD病理的MSA相比 控制力。具体来说，我们检验了AD+aSyn、PD、LBD和MSA是由不同的aSyn引起的这一新假设 从AD+aSyn和LBD脑中分离到aSyn-LB型菌株，而从PD脑中分离到aSyn-LB型 而来自MSA大脑的aSyn-GCI菌株，介导了AD共同病理的发展。