Alpha-Synuclein Induced Network Hyperexcitability in Lewy Body Dementias

项目总结 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，有一些 目前还没有延缓或阻止LBD进展的治疗方法。与LBD相关的癫痫发作应该更多 注意，因为，尽管对患者有有害的影响，癫痫发作活动可能不被识别和 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能力 拒绝。我们的初步研究表明，刘易体的关键成分异常α-突触核蛋白(αS)， 导致先于癫痫活动的认知障碍。我们还发现αS依赖的突触和认知 缺陷和癫痫活动需要内源性tau的表达。这让人想起数据显示， 在阿尔茨海默病(AD)小鼠模型中，Tau依赖的认知缺陷和癫痫活动。 用抗癫痫药物预防癫痫活动可改善AD模型的记忆，而抗癫痫药物 目前正处于AD的早期临床试验阶段。然而，针对α的抗癫痫药物还没有得到很好的研究。 联核症。为了更好地确定癫痫发作活动在LBD中的作用，提出了以下目标：目标1， 确定癫痫样活动与αS依赖认知功能障碍之间的因果关系；目的2， 确定αS纤维接种PDD/DLB模型是否通过 癫痫样活动；以及目标3，定义导致癫痫样发作的回路和细胞信号机制 突变的αS模型中的活性。这项调查的结果可能导致新的策略，如抗癫痫 药物和降低tau水平，作为LBD的治疗方法。

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.