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α-突触核蛋白菌株和多样化的剧局病 项目II领导者：J.Q。 Trojanowski;共同研究员：V.M.-Y. Lee＆K。Luk 项目II摘要/摘要 第二个项目（以前是IV项目和重新编号II，以改善研究的流程） “阿尔茨海默氏病和相关痴呆症中α-核蛋白菌株中心” 宾夕法尼亚州（宾夕法尼亚州）佩雷尔曼医学院（PSOM）检验了异质性和 帕金森氏症的Lewy Bodies（LBS）和Neurotes（LNS）中α-核蛋白（ASYN）病理的进展 没有（PD）的疾病或具有LBS（DLB）的痴呆症和痴呆症以及阿尔茨海默氏病的疾病 （AD）ASYN（AD+ASYN）LBS和LNS共同病理代表不同神经元ASYN的传播 菌株1我们将这些菌株彼此比较，并与来自多个系统萎缩（MSA）的ASYN菌株进行比较 神经胶质细胞质内包含（GCI）很少出现在AD中或与LBS/LN结合使用。这将进步 了解AD+ASYN与PD与PDD相对于DLB与MSA Drive临床和 这些疾病的病理异质性。自PDD和DLB中的痴呆症以来，称为LB痴呆症 （LBD），经常伴有AD的副病理，包括Aβ淀粉样蛋白斑和神经原纤维TAU 夹杂物和50％的AD患者患有LBS，我们还测试了以下假设：PDD与DLB与DLB相比 AD+Asyn大脑诱导Aβ和TAU病理学 病理可能不会。项目II与项目I合作，该项目在体外进行体外菌株研究和 提供项目II具有高度特征和经过验证的ASYN菌株AD+ASYN，PD，LBD MSA大脑以及体外扩增的LB和GCI ASYN菌株。对于这些研究，生活学科是 在核心B和项目III/IV及其大脑中进行了研究，核心D提供了数据 管理，生物统计学和生物信息学支持。突触核苷模型的程度 在项目II中对LB和GCI ASYN菌株的脑内注射诱导的对应于正宗人 将评估AD+ASYN vs PD与LBD与MSA。那就是II项目与所有U19中心紧密合作 与PD vs AD+Asyn vs LBD大脑相比 MSA GCI ASYN菌株（ASYN-GCI）差异地诱导神经元与神经胶质的病理ASYN以及 招募类似AD的Aβ和TAU沉积物或其他神经退行性疾病司法病理（例如TDP-43）。这 将这些ASYN菌株注射到野生型（WT）小鼠后，将完成脑内wt Asyn 小鼠Asyn敲出（KO）背景（KO61）和CNP-ASYN（M2）TG上的转基因（TG）小鼠（第61行）（第61行） 具有ASYN KO背景（KOM2）的小鼠与AD样Aβ的TG小鼠模型相比，该模型 斑块（5xFAD，TG2576，小鼠的APP敲击）和AD类Tau病理的TG小鼠模型（PS19系）。 在项目II中检验的假设来自于脑内注射的初步研究 Asyn将原纤维（PFF）纳入其中一些模型，我们现在通过注入不同的真实性来进行创新 人脑衍生的Asyn-LB和Asyn-GCI（包括最近开发了更多潜在的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 与缺乏AD病理学的MSA相比，AD+ASYN与PD与LBD的临床病理异质性 控制。特别是，我们检验了新的假设，即AD+ASYN，PD，LBD和MSA由不同的ASYN产生 菌株以及来自AD+ASYN和LBD大脑的ASYN-LB菌株，而不是PD脑中的Asyn-Lb菌株 以及来自MSA大脑的Asyn-GCI菌株，媒体的媒体发展。