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 多达60％的阿尔茨海默氏病（AD）患者表现出癫痫发作和网络多动症，导致 更快的认知能力下降。因此，AD中的癫痫发作应该是治疗干预措施的重要重点。 微管相关蛋白Tau是AD发病机理的核心因素，介导癫痫发作和相关 AD模型中的记忆丧失，表明靶向TAU可以有效地治疗AD中的癫痫发作。但是，那里 是理解Tau如何促进这些模型中的癫痫发作的根本差距。广泛减少tau 水平成功阻止癫痫发作；但是，减少tau还会在老年小鼠和 这种方法在成年人大脑中的安全性尚不清楚。因此，更好地理解如何 为了开发针对TAU的更精确的疗法，需要为癫痫发作做出贡献。总体目标 这是为了确定tau介导的癫痫发作和相关功能缺陷的机制 AD和遗传癫痫的适用的已获得的初步数据，表明阻止了tau的互动 使用SRC同源性3（SH3）含有蛋白质可以防止癫痫发作和相关的AD记忆丧失。这 基于申请人的初步数据的中心假设是，tau与含SH3的酶结合了它 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。对此概念的支持，先前的研究表明，tau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，以表明结合tau的其他含SH3的酶 参与了这一现象。拟议研究的理由是，一旦已知哪种酶 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 从药理学上，为预防和治疗癫痫发作和治疗带来了新的和创新的方法 相关的AD内存丢失。在强大的初步数据的指导下，适用的创建了两个小说 突变的tau敲蛋白小鼠模型，该假设将通过追求两个具体目的来检验：1）确定 变体在tau富含脯氨酸的区域中的影响，以防止其与含SH3的酶结合在 由Aβ低聚物引发的信号转导，它们是与AD相关的癫痫发作和兴奋毒素， 2）确定TAU中这些变体在多大程度上防止癫痫发作，行为定义和过早 AD和遗传癫痫的小鼠模型中的死亡率。拟议的研究具有创新性，因为它 通过将重点转移到tau的上游调制单元格，代表了与现状的实质性偏离 与Aβ和兴奋性毒性相关的信号传导。预计这项贡献将是重要的，因为它将具有广泛的 转化在预防和治疗AD中的癫痫发作和相关记忆丧失方面的重要性。