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

项目总结 高达60%的阿尔茨海默病(AD)患者出现癫痫发作和网络多动，导致 认知能力下降的速度更快。因此，阿尔茨海默病的发作应成为治疗干预的重要焦点。 微管相关蛋白tau是AD发病机制中的中心因子，介导癫痫发作和相关的 AD模型中的记忆丧失，提示靶向tau可以有效治疗AD的癫痫发作。然而，在那里 是理解tau如何在这些模型中导致癫痫发作的一个根本差距。广泛降低Tau 水平成功地防止了癫痫发作；然而，降低tau也会对老龄小鼠和 这种方法在成人大脑中的安全性尚不清楚。因此，更好地了解tau是如何 为了开发针对tau的更精确的治疗方法，需要有促进癫痫发作的药物。总体目标 这是为了确定tau在小鼠模型中调节癫痫发作和相关功能缺陷的机制。 阿尔茨海默病和遗传性癫痫。申请人已获得初步数据，表明阻止tau的相互作用 含有SRC同源3(SH3)的蛋白质可以防止AD的癫痫发作和相关的记忆丧失。这个 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。 并通过调节这些区域的活性或细胞定位来调节网络活动 酵素。以前的研究支持这一概念，已经表明tau和酪氨酸之间的结合 调节兴奋性受体的激酶Fyn参与了tau调节癫痫发作的能力。申请人的 初步数据在这些发现的基础上进行了扩展，表明其他含有SH3的酶与tau结合，并 卷入这一现象的。提出这项研究的理由是，一旦知道哪些酶 对tau介导癫痫发作的能力很重要，tau与这些酶的结合亲和力是可以操纵的 在药理学上，产生了预防和治疗癫痫的新的和创新的方法 阿尔茨海默病的相关记忆丧失。以强有力的初步数据为指导，在这些数据中，申请人创作了两部小说 突变的tau基因敲击小鼠模型，这一假说将通过追求两个特定目标来验证：1)确定 Tau富含脯氨酸区的变异体阻止其与含SH3酶结合的影响 由与AD相关的致痫多肽Aβ寡聚体和兴奋性毒素启动的信号转导 以及2)确定tau的这些变体在多大程度上预防癫痫发作、行为缺陷和早产 阿尔茨海默病和遗传性癫痫小鼠模型的死亡率。这项拟议的研究具有创新性，因为它 通过将重点转移到tau对细胞的上游调制，代表了对现状的实质性偏离 与Aβ相关的信号转导与兴奋性毒性这一贡献预计将是重大的，因为它将具有广泛的 翻译在预防和治疗阿尔茨海默病癫痫发作和相关记忆丧失中的重要性。

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.