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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：
10625706
负责人：
AMY F.T. ARNSTEN
金额：
$ 41.59万
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10625706
关键词：
Acute Aging Alzheimer like pathology Alzheimer&apos s Disease Amyloid beta-Protein Antibodies Astrocytes Brain Calcium Signaling Chronic Cognition Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Disease Dose Drug Discovery Groups Elderly Enzyme Inhibition FOLH1 gene Glutamates Glutamic Acid Human Immunoelectron Microscopy Impaired cognition Inflammatory Label Ligands Memory Monkeys Nerve Degeneration Neurons Pathology Pharmaceutical Preparations Phase Positioning Attribute Potassium Channel Prevention strategy Primates Rattus Research Short-Term Memory Synapses Testing Therapeutic Work aged association cortex base cognitive function entorhinal cortex improved inhibitor metabotropic glutamate receptor 3 metabotropic glutamate receptors type 3 neuroinflammation novel pinacolyl methylphosphonic acid pre-clinical assessment side effect tau Proteins tau phosphorylation 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.

这项研究将测试一种保护高级认知和减少tau蛋白的新机制