Modeling Lewy body dementia in vivo: Towards a better understanding of alpha synuclein and Tau interaction in disease

路易体痴呆体内建模：更好地了解 α 突触核蛋白和 Tau 在疾病中的相互作用

• 批准号: 9975335
• 负责人: Marion Delenclos
• 金额: $ 15.65万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975335
• 关键词: Adult; Alzheimer' s Disease; Amyloid beta-Protein; Animal Behavior; Animal Model; Animals; Autopsy; Behavior; Behavioral; Biochemical; Biological Assay; Brain; Brain region; Capsid; Clinical; Communities; Dementia; Development; Disease; Event; Functional disorder; Goals; Histologic; Histology; In Vitro; Injections; Intravenous; Investigation; Lead; Lesion; Lewy Body Dementia; Lewy Body Disease; Lewy body pathology; Ligation; Modeling; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathogenicity; Pathologic; Pathology; Play; Predisposition; Process; Reporting; Research; Rodent Model; Role; Senile Plaques; Solubility; Symptoms; Tauopathies; Techniques; Technology; Testing; Toxic effect; Transgenic Animals; Transgenic Mice; Transgenic Model; adeno-associated viral vector; alpha synuclein; behavioral outcome; cognitive function; comorbidity; falls; hyperphosphorylated tau; in vivo; in vivo Model; insight; model development; motor deficit; mouse model; nervous system disorder; neuropathology; neurotoxicity; novel; overexpression; synuclein; synucleinopathy; tau Proteins; tau aggregation; tau interaction; tool

PROJECT SUMMARY/ABSTRACT Lewy body dementia (LBD) is a term used to encompass both Parkinson’s disease dementia (PDD) and dementia with Lewy body (DLB) disorders. They are the second most common type of dementia after Alzheimer’s disease but are yet often misdiagnosed. Indeed, LBD appears to fall somewhere in the middle of a disease spectrum ranging from Alzheimer’s to Parkinson’s disease. Despite abundant evidence of a central role for alpha-synuclein (αsyn) in LBD pathogenesis, evidence shows that tau lesions, such as hyper phosphorylated tau protein, often coexists in DLB and PDD brains. Comorbid αsyn and tau pathology may be critical for the formation of disease-specific pathogenic aggregates that determine susceptibility to developing disease. Post-mortem brain investigations have reported presence of tau oligomers colocalizing with αsyn oligomers and in vitro and in vivo studies demonstrated that αsyn and tau promote the fibrilization of one another. Yet, a major unanswered question in the field is what mechanisms underlie LBD and how αsyn/tau interplay influences neurodegenerative processes. Rodent models continue to play a key role in advancing our understanding of neurodegenerative disorders and are a valuable tool to decipher mechanism of diseases. Development of models recapitulating the comorbid pathology and differential clinical symptom onset of PDD and DLB will help the field to better understand LBD pathogenesis and the cellular mechanisms that lead to neurodegeneration. Herein, we propose to identify the role of in-vivo αsyn/tau crosstalk and help to elucidate how tau and αsyn exert their toxicity in de novo mouse models where temporally controlled co-pathology will be induced. Indeed we will use AAV vector technology to transduce tau or αsyn expression in the adult brain of transgenic animals already presenting or αsyn or tau pathology respectively. Overall, the objective is to identify if αsyn and tau interplay results in enhanced pathology and dysfunction in these two different animal models. To answer these questions behavioral, histological and biochemical analyses will be conducted. These approaches will yield important insight into αsyn/tau interaction in vivo and may have the potential to model PDD and DLB pathology independently.

项目总结/摘要 路易体痴呆（Lewy body dementia，LBD）是用于涵盖帕金森病痴呆（Parkinson's disease dementia，PDD）和帕金森病痴呆（Parkinson's disease dementia，PDD）的术语。 路易体痴呆（DLB）他们是第二种最常见的痴呆症， 阿尔茨海默病，但往往被误诊。事实上，LBD似乎落在中间的某个地方， 从阿尔茨海默氏症到帕金森氏症。尽管有大量证据表明 α-突触核蛋白（αsyn）在LBD发病机制中的作用，有证据表明tau病变，如高表达， 磷酸化的tau蛋白通常共存于DLB和PDD脑中。共病αsyn和tau病理可能是 对于形成疾病特异性病原体聚集体至关重要，所述聚集体决定对发展中疾病的易感性。 疾病尸检脑调查报告存在tau寡聚体与αsyn共定位 低聚物以及体外和体内研究表明，αsyn和tau促进其中一种的原纤维化 另然而，该领域的一个主要未回答的问题是LBD的机制是什么以及αsyn/tau是如何影响LBD的？ 相互作用影响神经退行性过程。 啮齿类动物模型在促进我们对神经退行性疾病的理解方面继续发挥关键作用， 是解读疾病机制的宝贵工具发展概括共病的模型 PDD和DLB的病理学和鉴别临床症状发作将有助于该领域更好地了解LBD 发病机制和导致神经变性的细胞机制。在此，我们建议确定 体内αsyn/tau串扰的作用，并有助于阐明tau和αsyn如何在从头小鼠中发挥其毒性 将诱导暂时受控的共同病理学的模型。事实上，我们将使用AAV载体技术， 已经存在αsyn或tau的转基因动物的成年脑中的tau或αsyn表达 病理学分别。总的来说，目标是确定αsyn和tau的相互作用是否会导致增强 病理学和功能障碍。为了回答这些问题， 将进行组织学和生物化学分析。这些方法将产生重要的洞察力， αsyn/tau相互作用在体内，并可能有潜力模型PDD和DLB病理独立。

项目成果

Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models.

• DOI: 10.3390/biomedicines11102863
• 发表时间: 2023-10-22
• 期刊: Biomedicines
• 影响因子: 4.7