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

摘要 阿尔茨海默病（AD）神经病理学主要由两种病理性AD蛋白，tau， 和β-淀粉样蛋白（AAPs），两者都诱导神经元过度兴奋，并被认为在神经元过度兴奋中发挥作用。 AD和癫痫的高共病率。Tau负荷及其脑区分布 在AD和AD患者中， 癫痫患者，使tau蛋白成为两种疾病中有吸引力的疾病修饰靶点。AD 与非AD患者相比，AD患者癫痫的发病率增加，我们最近 表明点燃癫痫发作可加重淀粉样病变，由哺乳动物介导， 在AD小鼠模型中雷帕霉素复合物1（mTORC 1）活化的靶点。解决如何 神经元过度活跃可以增加AD病理，我们建议使用tau接种方法 使用两种新的AD小鼠模型来确定后期癫痫发作对时空的影响， 病理性tau的积累。我们还将检验AD中tau蛋白的传递性 通过采用一种方法永久标记被激活的细胞， 在接种tau蛋白后点燃癫痫发作。这将使我们能够测量水平和空间， tau和AD病理在整个脑中的时间分布，以及基因和 单个神经元水平的蛋白表达。我们还将利用AD患者的人脑组织 有和没有癫痫发作史，以及对照，以验证在 小鼠模型。最后，考虑到我们先前关于 雷帕霉素，以及tau积累和传递通过癫痫发作加速的假设， 我们将使用两种tau接种小鼠模型来评估癫痫发作后 长期使用mTORC 1抑制剂雷帕霉素或抗癫痫药物左乙拉西坦治疗 减缓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.