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更高认知和减少tau的新型机制基于新进化的皮质的独特需求，衰老皮层的磷酸化神经元在阿尔茨海默氏病（AD）中最脆弱。这些电路是通过馈电的强大调节的营地-PKA-钙信号传导，由于年龄的增长而失调，导致：1）超级开放K+通道，减少神经元的发射和损害认知，以及2）TAU的磷酸化。早期的在老年大鼠缔合皮层中可以看到PKA的Tau磷酸化阶段，而更先进的阶段在老化的猴子皮质中可见，包括由AT8抗体标记的原纤维tau和参与Aβ 表达。拟议的研究将测试一种调节营地-PKA-钙信号传导的策略，以减少AD- 通过扩增谷氨酸代谢性的大脑自然受保护作用，就像衰老皮层中的病理一样受体3型（MGLUR3）。 MGLUR3对星形胶质细胞具有神经保护作用，额外的调节性对神经元的作用。新数据揭示了前额叶关联皮层（PFC）中突触后MGLUR3 调节营地-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-乙酰基体甲基 - 谷氨酸），通过抑制破坏NAAG的酶 GCPII（谷氨酸羧肽酶II）。 GCPII抑制剂正在开发以治疗炎症在I期人类测试中具有出色的耐受性和最小副作用的疾病。我们将观察是否 MGLUR3定位以调节原发性肠hin骨皮层（ERC）中Tau的CAMP-PKA磷酸化。 PFC电路在AD中最脆弱，以及GCPII抑制是否可以恢复神经元射击，改善认知功能，抑制tau的磷酸化，并减少老年大鼠和猴子的神经炎症。这项工作将确认并延长两种在结构上不同的GCPII抑制剂，2-MPPA和2--的效率。 PMPA，约翰·霍普金斯（John Hopkins）毒品发现小组正在开发。 AIM 1将使用双免疫电子显微镜确认MGLUR3已正确定位以调节Tau的CAMP-PKA磷酸化（PS214TAU）和AT8标记的Tau在老化的ERC和PFC谷氨酸能突触中。 AIM 2将测试是否 2-MPPA或2-PMPA的急性给药可增强与记忆相关的PFC神经元发射通过调节K+通道的营地开放营地，以及系统性管理是否可以改善认知在年迈的大鼠和猴子中，副作用最小。 AIM 3将测试最佳的慢性治疗 2-MPPA的剂量可在工作记忆中持续改善，并减少tau磷酸化和老化大鼠和猴子协会皮质的神经炎症。我们将有难得的机会看看是否老化猴子的慢性2-MPPA处理可降低纤纤含量的tau和Aβ的表达。初步数据表明，这些药物在认知方面产生非常强大的改善，没有证据表明副作用，通过可行的翻译应用来鼓励一种治疗策略。