Preventing Seizures and Associated Memory Loss in Alzheimer's Disease by Blocking Tau Interactions with SH3-containing Proteins

通过阻断 Tau 与含 SH3 蛋白的相互作用来预防阿尔茨海默病的癫痫发作和相关记忆丧失

• 批准号: 9817263
• 负责人: Keith Alan Vossel
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9817263
• 关键词: 1-Phosphatidylinositol 3-Kinase; Ablation; Adult; Affinity; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acid Substitution; Amino Acids; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Attention; Behavior; Behavioral; Binding; Binding Proteins; Biochemical; Biological Assay; Brain; Complement; Data; Disease; Electrophysiology (science); Enzymes; Epilepsy; Epileptogenesis; Excitatory Neurotoxins; Exhibits; Functional disorder; Genetic; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Human; Hyperactive behavior; Impaired cognition; J20 mouse; Knock-in; Knock-in Mouse; Knowledge; Lead; Ligation; Link; Longevity; MAPT gene; Magnetic Resonance Imaging; Measures; Mediating; Memory Loss; Mission; Modeling; Mus; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Names; Neurodegenerative Disorders; Neurons; Outcome; PLC gamma1; PXXP Motif; Pathogenesis; Patients; Peptides; Pharmacology; Predisposition; Premature Mortality; Prevention; Prevention approach; Preventive Intervention; Process; Proline-Rich Domain; Proteins; Proto-Oncogene Proteins c-fyn; Public Health; Recombinant Proteins; Regulatory Element; Research; Resistance; Safety; Seizures; Signal Transduction; Slice; Synapses; Tauopathies; Testing; Therapeutic Intervention; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Variant; Work; adverse outcome; aged; base; brain size; excitotoxicity; familial Alzheimer disease; glutamatergic signaling; innovation; knock-down; mouse model; neuronal excitability; novel; overexpression; prevent; protective effect; protein complex; receptor; response; synaptic function; targeted treatment; tau Proteins; tau interaction; tau mutation

PROJECT SUMMARY Up to 60% of patients with Alzheimer’s disease (AD) exhibit seizures and network hyperactivity, leading to a faster cognitive decline. Therefore, seizures in AD should be an important focus for therapeutic interventions. The microtubule-associated protein tau, a central factor in AD pathogenesis, mediates seizures and associated memory loss in models of AD, suggesting that targeting tau could effectively treat seizures in AD. However, there is a fundamental gap in understanding how tau contributes to seizures in these models. Broadly reducing tau levels successfully prevents seizures; however, reducing tau also causes deleterious effects in aged mice and the safety of this approach in the adult human brain is unknown. Therefore, a better understanding of how tau contributes to seizures is needed in order to develop more precise therapies targeting tau. The overall objective here is to identify a mechanism by which tau mediates seizures and related functional deficits in mouse models of AD and genetic epilepsy. The applicant has obtained preliminary data indicating that blocking tau’s interactions with SRC Homology 3 (SH3)-containing proteins can prevent seizures and associated memory loss in AD. The central hypothesis, based on the applicant’s preliminary data, is that tau binds to SH3-containing enzymes on its proline-rich region, and regulates network activity by modulating the activity or cellular localization of these enzymes. Previous studies, supportive of this concept, have indicated that binding between tau and the tyrosine kinase Fyn, which regulates excitatory receptors, are involved in tau’s ability to regulate seizures. The applicant’s preliminary data expands on these findings to indicate additional SH3-containing enzymes that bind tau and are involved in this phenomenon. The rationale for the proposed research is that, once it is known which enzymes are important for tau’s ability to mediate seizures, tau’s binding affinity with these enzymes can be manipulated pharmacologically, resulting in new and innovative approaches to the prevention and treatment of seizures and associated memory loss in AD. Guided by strong preliminary data in which the applicant created two novel mutant tau knockin mouse models, this hypothesis will be tested by pursuing two specific aims: 1) Determine the influence of variants in the proline-rich region of tau that prevent its binding to SH3-containing enzymes on signal transduction initiated by Aβ oligomers, which are epileptogenic peptides linked to AD, and excitotoxins, and 2) Determine the extent to which these variants in tau prevent seizures, behavioral deficits, and premature mortality in mouse models of AD and genetic epilepsy. The proposed research is innovative because it represents a substantive departure from the status quo by shifting focus to tau’s upstream modulation of cell signaling related to Aβ and excitotoxicity. This contribution is expected to be significant because it will have broad translational importance in the prevention and treatment of seizures and associated memory loss in AD.

项目概要 高达 60% 的阿尔茨海默病 (AD) 患者会出现癫痫发作和网络过度活跃，从而导致 认知能力下降更快。因此，AD 的癫痫发作应成为治疗干预的重点。 微管相关蛋白 tau 是 AD 发病机制的核心因素，介导癫痫发作和相关的 AD 模型中的记忆丧失，表明靶向 tau 蛋白可以有效治疗 AD 癫痫发作。然而，有 在理解这些模型中 tau 蛋白如何导致癫痫发作方面存在根本性的差距。广泛减少 tau 水平成功预防癫痫发作；然而，减少 tau 蛋白也会对老年小鼠产生有害影响 这种方法在成年人脑中的安全性尚不清楚。因此，更好地了解 tau 为了开发针对 tau 的更精确疗法，需要对癫痫发作做出贡献。总体目标 目的是确定 tau 介导小鼠模型癫痫发作和相关功能缺陷的机制 AD 和遗传性癫痫。申请人已获得初步数据表明阻断 tau 相互作用 含有 SRC 同源 3 (SH3) 的蛋白质可以预防 AD 中的癫痫发作和相关的记忆丧失。这 根据申请人的初步数据，中心假设是 tau 与其上含有 SH3 的酶结合 富含脯氨酸的区域，并通过调节这些区域的活性或细胞定位来调节网络活动 酶。先前的研究支持了这一概念，表明 tau 蛋白和酪氨酸之间的结合 调节兴奋性受体的激酶 Fyn 参与 tau 调节癫痫发作的能力。申请人的 初步数据扩展了这些发现，表明还有其他含有 SH3 的酶可以结合 tau，并且 参与这一现象。拟议研究的基本原理是，一旦知道哪些酶 对于 tau 介导癫痫发作的能力很重要，tau 与这些酶的结合亲和力可以被操纵 药理学上，产生了预防和治疗癫痫发作的新方法和创新方法 AD 相关的记忆丧失。在强有力的初步数据的指导下，申请人创造了两种新颖的 突变 tau 基因敲入小鼠模型中，该假设将通过追求两个特定目标进行检验：1) 确定 tau 富含脯氨酸区域的变异的影响，阻止其与含有 SH3 的酶结合 由 Aβ 寡聚物启动的信号转导，Aβ 寡聚物是与 AD 相关的致癫痫肽和兴奋毒素， 2) 确定 tau 蛋白变异在多大程度上预防癫痫发作、行为缺陷和早产儿 AD 和遗传性癫痫小鼠模型的死亡率。拟议的研究具有创新性，因为它 通过将焦点转移到 tau 的上游细胞调节上，代表了对现状的实质性背离 与 Aβ 和兴奋性毒性相关的信号传导。预计这一贡献将是巨大的，因为它将具有广泛的影响 在预防和治疗 AD 癫痫发作和相关记忆丧失方面具有重要意义。