Exploring the modulation of synaptic/extrasynaptic NMDAR balance as a novel therapeutic strategy in Alzheimer's disease and other neurodegenerations

探索突触/突触外 NMDAR 平衡的调节作为阿尔茨海默病和其他神经退行性疾病的新型治疗策略

• 批准号: 10655316
• 负责人: Antonio Sanz-Clemente
• 金额: $ 46.87万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655316
• 关键词: APP-PS1; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyotrophic Lateral Sclerosis; Apoptosis; Biochemistry; Cessation of life; Characteristics; Clinic; Clinical; Cognitive deficits; Data; Deterioration; Diffusion; Disease; Equilibrium; Event; Excitatory Amino Acid Antagonists; Functional disorder; Glutamate Receptor; Glutamates; Goals; Hippocampus; Huntington Disease; Impaired cognition; Lateral; Ligands; Link; Mediating; Microscopy; Modeling; Molecular; Multiple Sclerosis; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuropathy; Outcome; Parkinson Disease; Pathologic; Patients; Peptides; Pharmacology; Phase; Phase I/II Clinical Trial; Phosphorylation; Physiological; Population; Positioning Attribute; Post-Translational Protein Processing; Process; Protein phosphatase; Proteins; Proteomics; Publishing; Regulation; Role; Signal Transduction; Site; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic; Work; antitumor drug; behavior test; burden of illness; cancer therapy; casein kinase II; disability; efficacy testing; excitotoxicity; in vivo; inhibitor; innovation; mouse model; novel; novel strategies; novel therapeutic intervention; pharmacologic; postsynaptic; prevent; protein protein interaction; receptor; receptor expression; receptor function; segregation; side effect; therapeutically effective; tool; trafficking; translational impact

Excitotoxicity is defined as the deterioration of neuronal function/structure caused by excessive glutamatergic stimulation. It is a shared major pathological hallmark in many neurodegenerative diseases (ND), including Alzheimer’s disease (AD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Excitotoxicity is mostly mediated by the activation of the NMDA-type of glutamate receptors (NMDARs). However, the NMDAR function is indispensable for normal neuronal function. This conundrum is explained by the fact that NMDARs are segregated in two populations: synaptic (sNMDARs) and extrasynaptic (exNMDARs). While sNMDARs are linked to pro-survival signaling, over-activation of exNMDARs triggers excitotoxicity. Therefore, exNMDAR are obvious pharmacological targets in a broad range of ND and, in fact, blocking NMDAR activity strongly ameliorates cognitive defects in AD and HD mouse models. However, selective inhibition of exNMDARs is challenging, and the vast majority of NMDAR antagonists have failed in clinic due to side effects mediated by sNMDAR blockade. We propose to test a novel therapeutic strategy based on the fact that s- and exNMDARs are not independent populations. On the contrary, s- and exNMDARs pools are physiologically connected via lateral diffusion. We hypothesize that shifting the s/exNMDAR balance towards synaptic expression would be beneficial two-folds (i) promoting survival cascades (sNMDAR-mediated) and (ii) decreasing pro-death signaling (exNMDAR-mediated). We are ideally suited to test this strategy because we have previously identified several of the mechanisms controlling s/exNMDAR balance. Those include different protein interactions with the GluN2B-subunit of NMDARs and a particular phosphorylation on GluN2B (at S1480) that promotes sNMDAR clearance and receptor stabilization at extrasynaptic sites. The goal of this proposal is to validate the proof-of-principle that reducing excitotoxicity by preventing sNMDAR clearance and/or promoting exNMDAR reinsertion into synaptic sites is an effective therapeutic strategy in ND. In Aim 1, we will evaluate novel molecular tools to modulate s/exNMDAR balance in culture and in vivo, including (i) small interfering peptides (sIPs) and (ii) pharmacology to modulate GluN2B phosphorylation. Our study includes the repurposing of an anti-tumoral drug currently in phase 1/2 of clinical trial. Also, we will use proteomics to compare the posttranslational modification profile of s- vs. exNMDARs, aiming to identify novel mechanisms regulating the balance. In Aim 2, we will evaluate the suitability of this strategy as a common therapeutic strategy in ND. First, we will test the efficacy of our tools in ameliorating excitotoxicity-mediated pathological outcomes in several models of AD, both in culture and in vivo. Finally, we will use our strategy in primary cultures from models of HD (associated by excitotoxicity) and Parkinson’s disease (excitotoxicity is not a primary pathomechanism). If successful, this proposal, based on reducing excitotoxicity by regulating NMDAR trafficking but not by inhibiting NMDAR function, will have a groundbreaking translational impact on the identification of innovative therapeutics for a wide range of ND.

兴奋性毒性定义为因过量谷氨酸能引起的神经功能/结构恶化 它是许多神经退行性疾病（ND）的共同主要病理特征，包括 阿尔茨海默病 (AD)、亨廷顿病 (HD) 和肌萎缩侧索硬化症 (ALS) 是兴奋性毒性。 主要由 NMDA 型谷氨酸受体 (NMDAR) 的激活介导。 NMDAR 的功能对于正常的神经功能是不可或缺的。 分为两个群体：突触 (sNMDAR) 和突触外 (exNMDAR)。 exNMDAR 与促生存信号传导相关，过度激活会引发兴奋性毒性。 在广泛的 ND 中具有明显的药理靶点，并且事实上，强烈阻断 NMDAR 活性 改善 AD 和 HD 小鼠模型的认知缺陷。然而，exNMDAR 的选择性抑制是有限的。 具有挑战性，并且绝大多数NMDAR拮抗剂由于介导的副作用而在临床上失败 我们建议基于 s- 和 exNMDAR 的事实来测试一种新的治疗策略。 相反，s-和 exNMDAR 池在生理上通过 我们勇敢地将 s/exNMDAR 平衡转向突触表达。 双重有益：(i) 促进生存级联（sNMDAR 介导）和 (ii) 减少促死亡信号传导 （exNMDAR 介导）我们非常适合测试该策略，因为我们之前已经确定了几种策略。 控制 s/exNMDAR 平衡的机制包括不同的蛋白质与 s/exNMDAR 的相互作用。 NMDAR 的 GluN2B 亚基以及促进 sNMDAR 的 GluN2B 上​​的特定磷酸化（位于 S1480） 该提案的目的是验证通过阻止 sNMDAR 清除和/或促进 exNMDAR 重新插入来减少兴奋性毒性的原理证明。 进入突触位点是 ND 的有效治疗策略。在目标 1 中，我们将评估新的分子工具来治疗 ND。 调节培养物和体内的 s/exNMDAR 平衡，包括 (i) 小干扰肽 (sIP) 和 (ii) 调节 GluN2B 磷酸化的药理学我们的研究包括抗肿瘤药物的重新利用。 目前正处于临床试验的1/2期此外，我们将使用蛋白质组学来比较翻译后修饰。 s- 与 exNMDAR 的概况，旨在确定调节平衡的新机制。在目标 2 中，我们将。 评估该策略作为 ND 常见治疗策略的适用性 首先，我们将测试其疗效。 我们的工具可改善多种 AD 模型中兴奋性毒性介导的病理结果（均在培养中） 最后，我们将在 HD 模型（与兴奋性毒性相关）的原代培养物中使用我们的策略。 和帕金森氏病（兴奋性毒性不是主要的病理机制）。 通过调节 NMDAR 运输而不是通过抑制 NMDAR 功能来减少兴奋性毒性，将具有 对多种 ND 创新疗法的识别具有突破性的转化影响。

项目成果

Shed CNTNAP2 ectodomain is detectable in CSF and regulates Ca2+ homeostasis and network synchrony via PMCA2/ATP2B2.

脱落的 CNTNAP2 胞外域可在 CSF 中检测到，并通过 PMCA2/ATP2B2 调节 Ca2 稳态和网络同步。

• 发表时间: 2022-02-16
• 影响因子: 16.2
• 作者: Martín;Dos Santos, Marc;Culotta, Lorenza;Varea, Olga;Spielman, Benjamin P;Parnell, Euan;Forrest, Marc P;Gao, Ruoqi;Yoon, Sehyoun;McCoig, Emmarose;Jalloul, Hiba A;Myczek, Kristoffer;Khalatyan, Natalia;Hall, Elizabeth A
• 通讯作者: Hall, Elizabeth A