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蛋白病 项目 II 负责人：J.Q. 联合研究员：V.M.-Y Lee 和 K. Luk 项目二总结/摘要 这个新的 U19 项目中的项目 II（以前的项目 IV 和重新编号为 II 以改善研究流程） 阿尔茨海默病及相关痴呆症中的α-突触核蛋白菌株中心” 宾夕法尼亚州 (Penn) 佩雷尔曼医学院 (PSOM) 检验了异质性和 帕金森病路易体 (LB) 和神经突 (LN) 中 α-突触核蛋白 (aSyn) 病理学的进展 不伴有痴呆症 (PD) 或伴有痴呆症 (PDD) 和伴有 LB 的痴呆症 (DLB) 以及阿尔茨海默氏病 (AD) 与 aSyn (AD+aSyn) LB 和 LN 共同病理代表不同神经元 aSyn 的传播 1 我们将这些菌株相互比较，并与多系统萎缩 (MSA) 的 aSyn 菌株进行比较 神经胶质细胞质内含物 (GCI) 很少出现在 AD 中或与 LB/LN 结合使用，这将促进进展。 深入了解 AD+aSyn、PD、PDD、DLB、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自PDD和DLB痴呆以来，统称为LB痴呆。 (LBD)，经常伴有 AD 共同病理，包括 Aβ 淀粉样蛋白斑和神经原纤维 tau 包含物，并且 50% 的 AD 患者有 LB，我们还测试了以下假设：PDD 与 DLB 与 aSyn 菌株 AD+aSyn 大脑诱导 Aβ 和 tau 病理，而 PD 中的 aSyn 菌株与缺乏 AD 的 MSA 大脑相比 病理学可能不会。项目 II 与项目 I 合作，进行体外 aSyn 菌株研究和 为项目 II 提供来自死后 AD+aSyn、PD、LBD 的经过高度表征和验证的 aSyn 菌株 和 MSA 大脑以及体外扩增的 LB 和 GCI aSyn 菌株 对于这些研究，活体受试者是。 在Core B和Projects III/IV中研究，他们的大脑是通过Core C获得的，而Core D提供数据 管理、生物统计学和生物信息学支持突触核蛋白病模型的程度。 项目 II 中通过脑内注射 LB 和 GCI aSyn 菌株诱导的结果对应于真实的人类 AD+aSyn vs PD vs LBD vs MSA 因此，项目 II 与所有 U19 中心密切合作。 确定 PD、AD+aSyn 与 LBD 大脑中的 LB aSyn 菌株 (aSyn-LB) 是否与 MSA GCI aSyn 菌株 (aSyn-GCI) 在神经元与神经胶质细胞中差异诱导病理性 aSyn 招募 AD 样 Aβ 和 tau 沉积物或其他神经退行性疾病共病理，例如 TDP-43。 将这些 aSyn 菌株脑内注射到野生型 (WT) 小鼠、人类 WT aSyn 中后进行 小鼠 aSyn 敲除 (KO) 背景 (KO61) 和 CNP-aSyn (M2) Tg 的转基因 (Tg) 小鼠（第 61 系） 与 AD 样 Aβ 的 Tg 小鼠模型相比，具有 aSyn KO 背景 (KOM2) 的 GCI 模型小鼠 斑块（5xFAD、Tg2576、APP 敲入小鼠）和 AD 样 tau 病理的 Tg 小鼠模型（PS19 系）。 项目 II 中测试的假设来自于脑内注射合成药物的初步研究 aSyn 将预制原纤维 (PFF) 植入其中一些模型中，我们现在通过注入不同的真实原纤维进行创新 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）进入我们的模型，以阐明不同 aSyn 菌株介导的基础 与缺乏 AD 病理学的 MSA 相比，AD+aSyn、PD、LBD 的临床病理异质性如下： 具体来说，我们测试了 AD+aSyn、PD、LBD 和 MSA 由不同 aSyn 产生的新假设。 菌株以及来自 AD+aSyn 和 LBD 大脑的 aSyn-LB 菌株，但不是来自 PD 大脑的 aSyn-LB 菌株 以及来自 MSA 大脑的 aSyn-GCI 菌株介导 AD 共同病理的发展。