Project II "aSyn Strains & Diverse Synucleinopathies"

项目二“aSyn菌株

• 批准号: 10654805
• 负责人: JOHN Q. TROJANOWSKI
• 金额: $ 45.8万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654805
• 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; Collaborations; Complement; Core Grant; Cytoplasmic Inclusion; Data; Dementia; Dementia with Lewy Bodies; Deposition; Development; Disease; Follow-Up Studies; Grant; Heterogeneity; Hippocampus; 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; Neurodegenerative Disorders; Neuroglia; Neurons; Parkinson Disease; Pathologic; Pathology; Pennsylvania; Property; Protein Precursors; Research; Research Personnel; 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; pre-formed fibril; 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-突触核蛋白菌株和各种突触核蛋白病 项目II负责人：J.Q. Trojanowski;合作研究者：V.M.- Y. Lee & K.陆 项目II概要/摘要 项目II（原项目IV，重新编号为II，以改善研究流程） “阿尔茨海默病和相关痴呆症中的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）测试了异质性和 帕金森氏病路易体和神经突中α-突触核蛋白病理学的进展 不伴痴呆（PD）或伴痴呆（PDD）的疾病和伴LB的痴呆（DLB），以及阿尔茨海默病 (AD)对于aSyn（AD+aSyn），LB和LN共同病变代表不同神经元aSyn的扩散， 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。 胶质细胞胞质内含物（GCI），其在AD或与LB/LN组合中很少出现。这将推动 深入了解AD+aSyn vs PD vs PDD vs DLB vs MSA中不同的aSyn菌株如何驱动临床和 这些疾病的病理异质性。由于PDD和DLB痴呆，简称LB痴呆 (LBD)通常伴有AD共病，包括Aβ淀粉样蛋白斑块和神经胶质tau蛋白 包含物，并且50%的AD患者患有LB，我们还检验了PDD vs DLB vs AD+aSyn脑诱导Aβ和tau病理，而PD中的aSyn菌株与缺乏AD的MSA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， 为项目II提供来自死后AD+aSyn、PD、LBD的高度表征和验证的aSyn菌株 和MSA脑以及体外扩增的LB和GCI aSyn菌株。在这些研究中， 在核心B和项目III/IV中研究，它们的大脑通过核心C获得，而核心D提供数据 管理、生物统计和生物信息学支助。突触核蛋白病模型 项目II中脑内注射LB和GCI aSyn菌株诱导的诱导与真实的人类相对应 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，以确定来自PD vs AD+aSyn vs LBD脑的LB aSyn菌株（aSyn-LB）与来自AD+aSyn vs LBD脑的LB aSyn菌株（aSyn-LB）相比， MSA GCI aSyn菌株（aSyn-GCI）在神经元与神经胶质中差异性地诱导病理性aSyn， 募集AD样Aβ和tau沉积物或其他神经退行性疾病共病，如TDP-43。这 将在脑内注射这些aSyn菌株至野生型（WT）小鼠、人WT aSyn后进行 在小鼠aSyn敲除（KO）背景（KO 61）上的转基因（Tg）小鼠（品系61）和CNP-aSyn（M2）Tg 与AD样Aβ的Tg小鼠模型相比，具有aSyn KO背景的小鼠（KOM 2）模拟GCI 噬斑（5xFAD，Tg 2576，小鼠中的APP敲除）和AD样tau病理的Tg小鼠模型（PS19系）。 在项目II中检验的假设来自于对脑内注射合成 aSyn预成型纤维（PFF）到这些模型中的一些，我们现在通过注入不同的真实的创新， 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）引入我们的模型中，以阐明不同aSyn菌株介导的 与缺乏AD病理学的MSA相比，AD+aSyn vs PD vs LBD的临床病理学异质性， 控制具体地，我们检验了AD+aSyn、PD、LBD和MSA由不同aSyn引起的新假设。 菌株以及来自AD+aSyn和LBD脑的aSyn-LB菌株，但不是来自PD脑的aSyn-LB菌株 和来自MSA脑的aSyn-GCI菌株介导AD共病理的发展。