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: 10455852
• 负责人: Frances E Jensen
• 金额: $ 67.4万
• 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/10455852
• 关键词: 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; 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 (Brain); Human; Hyperactivity; Immediate-Early Genes; Impaired cognition; Incidence; Label; Levetiracetam; Light; Maps; Measures; Mediating; Metabolism; Methods; Modification; Molecular; Mus; Nerve Degeneration; Neurons; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Pentylenetetrazole; Persons; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Positron-Emission Tomography; Process; Proteins; Recording of previous events; Role; Seeds; 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; dementia risk; efficacy testing; high risk; human tissue; 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 阿尔茨海默氏病（AD）神经病理学主要由两种病理AD蛋白，Tau，Tau， 和β-淀粉样蛋白（Aß），两者都诱导神经元过度兴奋性，被认为起作用 在AD和癫痫之间的高合并症中。 tau负载及其区域大脑分布 与AD和 癫痫患者，使Tau成为两种情况下疾病修饰的有吸引力的靶标。广告 与非AD患者相比，患者患癫痫的事件增加了，我们最近 表明点燃的癫痫发作会加剧由哺乳动物介导的淀粉样病理学 AD小鼠模型中雷帕霉素复合物1（MTORC1）激活的靶标。解决如何 神经元多动症可以增加AD病理，我们建议使用tau播种方法 使用两个新型的AD小鼠模型来确定后来的癫痫发作对时空的影响 病理tau的积累。我们还将检验以下假设 通过将方法调整以永久性标记细胞激活，通过突触激活发生 tau播种后点燃的癫痫发作。这将使我们能够测量水平和空间和 TAU和AD病理的暂时分布在整个大脑以及基因和基因和基因 单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 有和没有癫痫病史和对照，以验证在 鼠标模型。最后，鉴于我们先前关于有关治疗作用的观察 雷帕霉素，以及通过癫痫发作加速tau加速和传播的假设， 我们将使用两个TAU播种小鼠模型来评估塞兹后的治疗效率 用MTORC1抑制剂雷帕霉素或固定剂左乙拉氏菌中的慢性治疗 衰减广告进展。