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Preclinical assessment of GCPII inhibitors for cognition and tau pathology

GCPII 抑制剂对认知和 tau 病理学的临床前评估

基本信息

批准号：
10541131
负责人：
AMY F.T. ARNSTEN
金额：
$ 60.11万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541131
关键词：
Abbreviations Acute Aging Alzheimer disease prevention Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Amyloid beta-Protein Animals Antibodies Astrocytes Biological Assay Blood Blood drug level result Brain Calcium Signaling Charge Chronic Cognition Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Disease Dose Drug Discovery Groups Elderly Enzyme Inhibition Enzymes FOLH1 gene Glutamates Glutamic Acid Hippocampus Human Immunoelectron Microscopy Impaired cognition In Vitro Inflammatory Label Late Onset Alzheimer Disease Ligands Location Membrane Memory Molecular Monkeys Nerve Degeneration Neurons Pathology Pharmaceutical Preparations Phase Phosphorylation Inhibition Positioning Attribute Potassium Channel Prefrontal Cortex Prevention strategy Primates Rattus Regulation Research Risk Reduction Short-Term Memory Signal Transduction Smooth Endoplasmic Reticulum Synapses Testing Therapeutic Translating Translations Work age related aged amyloid pathology association cortex cognitive enhancement cognitive function cognitive performance drug development drug discovery entorhinal cortex experimental study improved inhibitor metabotropic glutamate receptor 3 metabotropic glutamate receptors type 3 neuroinflammation neuroprotection novel pinacolyl methylphosphonic acid postsynaptic pre-clinical assessment side effect tau Proteins tau-1 therapeutic target therapy development translational applications

项目摘要

The proposed research will test a novel mechanism for protecting higher cognition and reducing tau phosphorylation in the aging cortex, based on the unique needs of the newly evolved association cortical neurons most vulnerable in Alzheimer's Disease (AD). These circuits are powerfully modulated by feedforward, cAMP-PKA-calcium signaling, which becomes dysregulated with advancing age, leading to: 1) excessive opening of K+ channels, reducing neuronal firing and impairing cognition, and 2) phosphorylation of tau. Early stages of tau phosphorylation by PKA can be seen in aged rat association cortex, while more advanced stages are seen in aged monkey cortex, including fibrillated tau labeled by the AT8 antibody, and accompanying Aβ expression. The proposed research will test a strategy to regulate cAMP-PKA-calcium signaling to reduce AD- like pathology in the aging cortex by amplifying the brain's natural protective actions at glutamate metabotropic receptors type 3 (mGluR3). mGluR3 have neuroprotective actions on astrocytes, and additional, regulatory actions on neurons. New data have revealed post-synaptic mGluR3 in prefrontal association cortex (PFC) that regulate cAMP-PKA-calcium signaling. The proposed research will enhance stimulation of mGluR3 by its endogenous ligand, NAAG (N-acetylaspartyl-glutamic acid), via inhibition of the enzyme that destroys NAAG, GCPII (glutamate carboxypeptidase II). GCPII inhibitors are under development for treating inflammatory disorders, with excellent tolerability and minimal side effects in phase I human testing. We will observe whether mGluR3 are positioned to regulate cAMP-PKA phosphorylation of tau in the primate entorhinal cortex (ERC) and PFC circuits most vulnerable in AD, and whether GCPII inhibition can restore neuronal firing, improve cognitive function, inhibit phosphorylation of tau, and reduce neuroinflammation in aged rats and monkeys. This work will confirm and extend the efficacy of two structurally distinct GCPII inhibitors, 2-MPPA and 2- PMPA, under development by the Johns Hopkins Drug Discovery group. Aim 1 will use dual immunoelectron microscopy to confirm that mGluR3 are correctly positioned to regulate cAMP-PKA phosphorylation of tau (pS214Tau) and AT8-labeled tau in aging ERC and PFC glutamatergic synapses. Aim 2 will test whether acute administration of 2-MPPA or 2-PMPA enhances memory-related PFC neuronal firing in aging monkeys by regulating cAMP-PKA opening of K+ channels, and whether systemic administration can improve cognition in aged rats and monkeys with minimal side effects. Aim 3 will test whether chronic treatment with an optimal dose of 2-MPPA produces sustained improvement in working memory, and reduces tau phosphorylation and neuroinflammation in aged rat and monkey association cortex. We will have the rare opportunity to see if chronic 2-MPPA treatment in aged monkeys reduces both fibrillated AT8-labeled tau, and Aβ expression. Preliminary data indicate that these agents produce very robust improvements in cognition with no evidence of side effects, encouraging a therapeutic strategy with feasible translational application.

拟议的研究将测试一种保护高级认知和减少 tau 蛋白的新机制老化皮质中的磷酸化，基于新进化的联合皮质的独特需求神经元在阿尔茨海默病（AD）中最脆弱。这些电路通过前馈进行强大的调制， cAMP-PKA-钙信号传导，随着年龄的增长而失调，导致：1) 过度打开 K+ 通道，减少神经元放电并损害认知，2) tau 磷酸化。早期的 PKA 的 tau 磷酸化阶段可以在老年大鼠关联皮层中看到，而更高级的阶段在老年猴子皮层中可见，包括 AT8 抗体标记的纤维化 tau 蛋白以及伴随的 Aβ 表达。拟议的研究将测试调节 cAMP-PKA-钙信号传导以减少 AD-的策略。通过增强大脑对谷氨酸代谢的自然保护作用，类似于衰老皮质中的病理学 3 型受体 (mGluR3)。 mGluR3 对星形胶质细胞具有神经保护作用，并且具有额外的调节作用对神经元的作用。新数据揭示了前额叶关联皮层 (PFC) 中的突触后 mGluR3 调节 cAMP-PKA-钙信号传导。拟议的研究将通过其增强 mGluR3 的刺激内源性配体 NAAG（N-乙酰天冬氨酰-谷氨酸），通过抑制破坏 NAAG 的酶， GCPII（谷氨酸羧肽酶 II）。 GCPII 抑制剂正在开发用于治疗炎症在 I 期人体测试中具有出色的耐受性和最小的副作用。我们将观察是否 mGluR3 负责调节灵长类动物内嗅皮层 (ERC) 中 tau 蛋白的 cAMP-PKA 磷酸化和 PFC 电路在 AD 中最脆弱，抑制 GCPII 是否可以恢复神经元放电、改善认知功能，抑制 tau 蛋白磷酸化，并减少老年大鼠和猴子的神经炎症。这项工作将确认并扩展两种结构不同的 GCPII 抑制剂 2-MPPA 和 2- 的功效。 PMPA，由约翰·霍普金斯大学药物发现小组正在开发。目标1将使用双免疫电子显微镜确认 mGluR3 正确定位以调节 tau 的 cAMP-PKA 磷酸化 (pS214Tau) 和 AT8 标记的 tau 蛋白存在于衰老的 ERC 和 PFC 谷氨酸能突触中。目标 2 将测试是否急性施用 2-MPPA 或 2-PMPA 可增强衰老猴子中与记忆相关的 PFC 神经元放电通过调节cAMP-PKA打开K+通道，以及全身给药是否可以改善认知在老年大鼠和猴子中，副作用最小。目标 3 将测试长期治疗是否具有最佳效果 2-MPPA 剂量可持续改善工作记忆，并减少 tau 磷酸化和老年大鼠和猴子联合皮层的神经炎症。我们将有难得的机会来看看对老年猴子进行长期 2-MPPA 治疗可减少原纤维化 AT8 标记的 tau 蛋白和 Aβ 表达。初步数据表明，这些药物对认知产生了非常强劲的改善，但没有证据表明副作用，鼓励具有可行转化应用的治疗策略。