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.

项目摘要 高达60%的阿尔茨海默病（AD）患者表现出癫痫发作和网络活动过度， 更快的认知衰退。因此，AD的癫痫发作应成为治疗干预的重要焦点。 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疾病 AD模型中的记忆丧失，表明靶向tau可以有效治疗AD中的癫痫发作。但 是理解tau蛋白如何在这些模型中促进癫痫发作的根本差距。广泛减少tau 水平成功地预防癫痫发作;然而，减少tau蛋白也会对老年小鼠产生有害影响， 这种方法在成人大脑中的安全性是未知的。因此，更好地了解tau 为了开发更精确的靶向tau蛋白的治疗方法，总体目标 本研究旨在确定tau蛋白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 与SRC同源3（SH 3）蛋白的结合可以预防AD中的癫痫发作和相关的记忆丧失。的 基于申请人的初步数据，中心假设是tau结合其上的含SH 3的酶， 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性。 内切酶先前的研究支持这一概念，已经表明tau蛋白和酪氨酸蛋白之间的结合， 调节兴奋性受体的Fyn激酶参与tau蛋白调节癫痫发作的能力。申请人的 初步数据扩展了这些发现，表明另外的含有SH 3的酶结合tau蛋白， 参与这一现象。这项研究的基本原理是，一旦知道哪些酶 对于tau介导癫痫发作的能力是重要的，可以操纵tau与这些酶的结合亲和力 从而产生了预防和治疗癫痫发作的新的创新办法， 与AD相关的记忆丧失在强有力的初步数据的指导下，申请人创造了两个新的 突变tau基因敲入小鼠模型，该假设将通过追求两个具体目标来测试：1）确定 tau蛋白富含脯氨酸的区域中阻止其与含SH 3的酶结合的变体对 由Aβ寡聚体（与AD相关的致痫肽）和兴奋性毒素启动的信号转导， 和2）确定tau蛋白中的这些变异体在多大程度上预防癫痫发作、行为缺陷和早产。 AD和遗传性癫痫小鼠模型的死亡率。这项研究是创新的，因为它 通过将焦点转移到tau蛋白对细胞的上游调节， 与Aβ和兴奋性毒性相关的信号传导。预计这一贡献将是重大的，因为它将具有广泛的 在预防和治疗AD中的癫痫发作和相关记忆丧失中的重要性。