Seizure-induced enhancement of synaptic signaling regulating tau transmissibility in Alzheimer's Disease

摘要 阿尔茨海默病(AD)的神经病理很大程度上是由两种病理性AD蛋白，tau， 和β-淀粉样蛋白(Aü)，这两种物质都能诱导神经元过度兴奋，并被认为在 在阿尔茨海默病和癫痫的高度共病中。Tau负荷及其脑内区域分布 在AD和AD患者中，与淀粉样斑块沉积相比，与认知能力下降的相关性更密切 在这两种情况下，tau都是有吸引力的疾病改良物。广告 与非阿尔茨海默病患者相比，患者癫痫的发生率有所增加，我们最近 表明点燃的癫痫可以加重淀粉样蛋白的病理，由哺乳动物介导 雷帕霉素复合体1(MTORC1)在AD小鼠模型中的激活靶点。要解决如何 神经元过度活跃可以增加AD的病理，我们建议使用tau种子方法 用两种新的AD小鼠模型来确定晚期癫痫发作对时空的影响 病理性tau的堆积。我们还将检验tau在AD中的遗传性假设 通过采用一种永久标记由 在tau播种后点燃癫痫发作。这将使我们能够测量水平和空间以及 Tau和AD病理在整个大脑中的时间分布，以及基因和 单个神经元水平的蛋白质表达。我们还将利用AD患者的人脑组织 有和没有癫痫史和对照，以验证观察到的分子变化 老鼠模型。最后，考虑到我们之前观察到的关于 雷帕霉素，以及tau的积累和传输因癫痫发作而加速的假说， 我们将使用两种tau种子小鼠模型来评估癫痫发作后的治疗效果。 MTORC1抑制剂雷帕霉素或抗癫痫药物左乙拉西坦治疗慢性癫痫 延缓AD进展。

Abstract Alzheimer’s Disease (AD) neuropathology is largely driven by two pathological AD proteins, tau, and ß-amyloid (Aß), both of which induce neuronal hyperexcitability and are thought to play a role in the high comorbidity between AD and epilepsy. Tau load and its regional brain distribution correlate more closely with cognitive decline than amyloid plaque deposition in both AD and epilepsy patients, making tau an attractive target for disease modification in both conditions. AD patients have an increased incidence of epilepsy compared to non-AD patients, and we recently showed that kindled seizures can exacerbate amyloid pathology, mediated by the mammalian target of rapamycin complex 1 (mTORC1) activation in an AD mouse model. To address how neuronal hyperactivity can increase AD pathology, we propose to use a tau seeding approach using two novel AD mice models to determine the effects of later seizures on the spatiotemporal accumulation of pathologic tau. We will also test the hypothesis that tau transmissibility in AD occurs through synaptic activation by adapting a method to permanently label cells activated by kindled seizures following tau seeding. This will allow us to measure the levels and spatial and temporal distribution of tau and AD pathology throughout the entire brain, as well as gene and protein expression at single neuron level. We will also utilize human brain tissue from AD patients with and without a seizure history, and controls, to validate molecular changes observed in the mouse models. Finally, given our prior observations regarding the therapeutic effects of rapamycin, and the hypothesis that tau accumulation and transmission is accelerated by seizures, we will use the two tau seeding mouse models to assess the therapeutic efficacy of post-seizure chronic treatment with the mTORC1 inhibitor rapamycin or the antiseizure drug levetiracetam in attenuating AD progression.