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:
- 金额:$ 60.11万
- 依托单位:
- 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:
- 关键词:AbbreviationsAcuteAgingAlzheimer disease preventionAlzheimer like pathologyAlzheimer&aposs DiseaseAlzheimer&aposs disease diagnosisAmyloid beta-ProteinAnimalsAntibodiesAstrocytesBiological AssayBloodBlood drug level resultBrainCalcium SignalingChargeChronicCognitionCyclic AMPCyclic AMP-Dependent Protein KinasesDataDevelopmentDiseaseDoseDrug Discovery GroupsElderlyEnzyme InhibitionEnzymesFOLH1 geneGlutamatesGlutamic AcidHippocampusHumanImmunoelectron MicroscopyImpaired cognitionIn VitroInflammatoryLabelLate Onset Alzheimer DiseaseLigandsLocationMembraneMemoryMolecularMonkeysNerve DegenerationNeuronsPathologyPharmaceutical PreparationsPhasePhosphorylation InhibitionPositioning AttributePotassium ChannelPrefrontal CortexPrevention strategyPrimatesRattusRegulationResearchRisk ReductionShort-Term MemorySignal TransductionSmooth Endoplasmic ReticulumSynapsesTestingTherapeuticTranslatingTranslationsWorkage relatedagedamyloid pathologyassociation cortexcognitive enhancementcognitive functioncognitive performancedrug developmentdrug discoveryentorhinal cortexexperimental studyimprovedinhibitormetabotropic glutamate receptor 3metabotropic glutamate receptors type 3neuroinflammationneuroprotectionnovelpinacolyl methylphosphonic acidpostsynapticpre-clinical assessmentside effecttau Proteinstau-1therapeutic targettherapy developmenttranslational 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('AMY F.T. ARNSTEN', 18)}}的其他基金
Prefrontal impairment with stress- NE receptor subtype mechanisms.
与压力-NE受体亚型机制有关的前额损伤。
- 批准号:
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- 资助金额:
$ 60.11万 - 项目类别:
Development of GCPII inhibitors for the treatment of age-related cognitive disorders
开发用于治疗年龄相关认知障碍的 GCPII 抑制剂
- 批准号:
10410566 - 财政年份:2020
- 资助金额:
$ 60.11万 - 项目类别:
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开发用于治疗年龄相关认知障碍的 GCPII 抑制剂
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10633273 - 财政年份:2020
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