Alpha-Synuclein Induced Network Hyperexcitability in Lewy Body Dementias

α-突触核蛋白诱导路易体痴呆的网络过度兴奋

• 批准号: 10470990
• 负责人: MICHAEL K LEE
• 金额: $ 84.03万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470990
• 关键词: Acute; Age; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Attention; Attenuated; Autopsy; Calcineurin; Chronic; Clinical; Cognitive deficits; Data; Dementia; Dementia with Lewy Bodies; Dendritic Spines; Dependence; Disease; Electrophysiology (science); Endocytosis; Epilepsy; Excitatory Synapse; Exhibits; FK506; Future; Hippocampus (Brain); Histologic; Human; Hyperactivity; Impaired cognition; Incidence; Investigation; Lead; Lewy Bodies; Lewy Body Dementia; Link; Mediating; Memory; Memory impairment; Modeling; Mus; Myoclonus; Neurons; Parkinson' s Dementia; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Population Control; Prosencephalon; Proteins; Role; Seizures; Signal Transduction; Sleep disturbances; Slice; Symptoms; Synapses; Testing; Transgenes; Transgenic Mice; Transgenic Model; alertness; alpha synuclein; attenuation; base; calmodulin-dependent protein kinase II; cell type; disability; early phase clinical trial; effective therapy; excitatory neuron; improved; inhibitory neuron; mouse model; mutant; neural network; overexpression; presynaptic; prevent; progressive neurodegeneration; screening; synucleinopathy; tau Proteins; tau expression; tau phosphorylation; therapy development; transmission process

PROJECT SUMMARY Lewy body dementias (LBD), including Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), are the second most common type of degenerative dementia in the world. Unfortunately, there are currently no therapies to slow or halt the progression of LBD. Seizures associated with LBD deserve more attention because, despite the harmful impact on the patients, seizure activity can go unrecognized and untreated. Seizures or myoclonus occur in over half of DLB patients, and these symptoms hasten cognitive decline. Our preliminary studies indicate that abnormal α-synuclein (αS), a key component of Lewy bodies, causes cognitive deficits preceded by epileptic activity. We also show that αS-dependent synaptic and cognitive deficits and epileptic activity require endogenous tau expression. This is reminiscent of data showing that the tau-dependence of cognitive deficits and epileptic activity in the mouse models of Alzheimer’s disease (AD). Preventing epileptic activity with antiseizure drugs improves memory in models of AD, and antiseizure drugs are currently in early phase clinical trials for AD. However, antiseizure drugs have not been well investigated for α- synucleinopathy. To better define the role of seizure activity in LBD, the following aims are proposed: Aim 1, Determine the causal relationship between the epileptiform activity and αS-dependent cognitive deficits; Aim 2, Determine if αS fibril inoculation model of PDD/DLB causes tau-dependent cognitive deficits mediated by epileptiform activity; and Aim 3, Define the circuitry and cellular signaling mechanisms contributing to epileptiform activity in mutant αS models. The results of this investigation could lead to new strategies, such as antiseizure drugs and reducing tau levels, as therapies for LBD.

项目概要 路易体痴呆 (LBD)，包括帕金森病痴呆 (PDD) 和路易体痴呆 （DLB）是世界上第二常见的退行性痴呆类型。不幸的是，有 目前尚无疗法可以减缓或阻止 LBD 的进展。与 LBD 相关的癫痫发作值得更多关注 引起注意，因为尽管癫痫发作对患者有有害影响，但癫痫发作活动可能会被忽视，并且 未经治疗。超过一半的 DLB 患者会出现癫痫发作或肌阵挛，这些症状会加速认知障碍 衰退。我们的初步研究表明，异常的α-突触核蛋白（αS）是路易体的关键组成部分， 导致癫痫活动之前的认知缺陷。我们还表明，αS 依赖性突触和认知 缺陷和癫痫活动需要内源性 tau 表达。这让人想起数据显示 阿尔茨海默病 (AD) 小鼠模型中认知缺陷和癫痫活动的 tau 依赖性。 使用抗癫痫药物预防癫痫活动可以改善 AD 模型的记忆力，并且抗癫痫药物是 目前正处于 AD 的早期临床试验阶段。然而，抗癫痫药物尚未针对 α- 进行充分研究。 突触核蛋白病。为了更好地定义癫痫发作活动在 LBD 中的作用，提出以下目标：目标 1， 确定癫痫样活动与αS依赖性认知缺陷之间的因果关系；目标2， 确定 PDD/DLB 的 αS 原纤维接种模型是否会导致 tau 依赖性认知缺陷介导 癫痫样活动；目标 3，定义导致癫痫样的电路和细胞信号传导机制 突变αS模型中的活性。这项调查的结果可能会带来新的策略，例如抗癫痫 药物和降低 tau 水平，作为 LBD 的治疗方法。

项目成果

Loss of tau expression attenuates neurodegeneration associated with α-synucleinopathy.

• DOI: 10.1186/s40035-022-00309-x
• 发表时间: 2022-07-01
• 期刊: TRANSLATIONAL NEURODEGENERATION
• 影响因子: 12.6
• 作者: Vermilyea, Scott C.;Christensen, Anne;Meints, Joyce;Singh, Balvindar;Martell-Martinez, Hector;Karim, Md. Razaul;Lee, Michael K.
• 通讯作者: Lee, Michael K.

Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms.

• DOI: 10.3389/fnagi.2022.903973
• 发表时间: 2022
• 期刊: Frontiers in aging neuroscience
• 影响因子: 4.8

Hippocampal subfield vulnerability to α-synuclein pathology precedes neurodegeneration and cognitive dysfunction.

海马亚区对α-突触核蛋白病理学的脆弱性先于神经变性和认知功能障碍。

• DOI: 10.1101/2023.04.12.536572
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Dues,DylanJ;Nguyen,AnPhuTran;Becker,Katelyn;Ma,Jiyan;Moore,DarrenJ
• 通讯作者: Moore,DarrenJ

Formation of templated inclusions in a forebrain α-synuclein mouse model is independent of LRRK2.

前脑 α-突触核蛋白小鼠模型中模板化内含物的形成独立于 LRRK2。

• DOI: 10.1101/2023.08.19.553965
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Dues,DylanJ;Ma,Yue;Nguyen,AnPhuTran;Offerman,AlinaV;Beddows,Ian;Moore,DarrenJ
• 通讯作者: Moore,DarrenJ