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

癫痫发作诱导的突触信号增强调节阿尔茨海默病中 tau 蛋白的传递性

• 批准号: 10611518
• 负责人: Frances E Jensen
• 金额: $ 72.06万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611518
• 关键词: Acceleration; Address; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Anticonvulsants; Antiepileptic Agents; Attenuated; Autopsy; Behavioral; Blood specimen; Brain; Brain Mapping; Brain region; Cell Separation; Cells; Chronic; Complex; Dementia; Deposition; Disease; Disease Progression; Distant; Elements; Epilepsy; Epitopes; Exhibits; FOS gene; FRAP1 gene; Fluorescence Microscopy; Gene Expression; Generations; Hippocampus; Human; Hyperactivity; Immediate-Early Genes; Impaired cognition; Incidence; Label; Late Effects; Levetiracetam; Light; Maps; Measures; Mediating; Metabolism; Methods; Modification; Molecular; Mus; Nerve Degeneration; Neurons; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Pentylenetetrazole; Persons; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Positron-Emission Tomography; Process; Proteins; Recording of previous events; Seizures; Senile Plaques; Severities; Signal Pathway; Signal Transduction; Sirolimus; Synapses; Synaptic Transmission; Synaptic Vesicles; Tamoxifen; Tauopathies; Testing; Therapeutic Effect; Tissue-Specific Gene Expression; Treatment Efficacy; Western Blotting; amyloid pathology; behavior test; brain tissue; clinical biomarkers; comorbidity; comparison control; dementia risk; efficacy testing; high risk; human tissue; hyperphosphorylated tau; inhibitor; innovation; interest; mind control; mouse model; neuron loss; neuropathology; neurotransmission; novel; novel therapeutic intervention; pre-clinical; protein expression; spatiotemporal; targeted treatment; tau Proteins; tau aggregation; tau expression; tau mutation; tau-protein kinase; transcriptome; transcriptome sequencing; transmission process; uptake; vesicular release

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.

抽象的 阿尔茨海默病 (AD) 神经病理学很大程度上是由两种病理性 AD 蛋白 tau、 和 β-淀粉样蛋白 (Aß)，两者都会引起神经元过度兴奋，并被认为在其中发挥作用 AD 和癫痫之间的高合并症及其脑区域分布。 在AD和AD中，与淀粉样斑块沉积相比，与认知能力下降的关系更为密切。 癫痫患者，使 tau 成为这两种疾病的疾病治疗的有吸引力的靶点。 与非 AD 患者相比，AD 患者的癫痫发病率有所增加，我们最近 研究表明，点燃的癫痫发作会加剧由哺乳动物介导的淀粉样蛋白病理学 AD 小鼠模型中雷帕霉素复合物 1 (mTORC1) 激活的靶标 神经元过度活跃会增加 AD 病理，我们建议使用 tau 播种方法 使用两种新型 AD 小鼠模型来确定后期癫痫发作对时空的影响 我们还将检验 AD 中 tau 传递性的假设。 通过采用一种方法永久标记由突触激活的细胞来发生 tau 播种后引发的癫痫发作这将使我们能够测量水平和空间以及 整个大脑中 tau 蛋白和 AD 病理学的时间分布，以及基因和 我们还将利用 AD 患者的人脑组织进行单神经元水平的蛋白质表达。 有或没有癫痫病史和对照，以验证观察到的分子变化 最后，考虑到我们之前对治疗效果的观察。 雷帕霉素，以及癫痫发作加速 tau 蛋白积累和传输的假设， 我们将使用两种tau蛋白接种小鼠模型来评估癫痫发作后的治疗效果 使用 mTORC1 抑制剂雷帕霉素或抗癫痫药左乙拉西坦进行长期治疗 减缓 AD 进展。