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衰老大鼠前额叶皮层中的谷氨酸羧肽酶II损害工作记忆表现。

Glutamate Carboxypeptidase II in Aging Rat Prefrontal Cortex Impairs Working Memory Performance.

作者信息

Datta Dibyadeep, Leslie Shannon N, Woo Elizabeth, Amancharla Nishita, Elmansy Ayah, Lepe Miguel, Mecca Adam P, Slusher Barbara S, Nairn Angus C, Arnsten Amy F T

机构信息

Department of Neuroscience, Yale University School of Medicine, New Haven, CT, United States.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.

出版信息

Front Aging Neurosci. 2021 Nov 15;13:760270. doi: 10.3389/fnagi.2021.760270. eCollection 2021.

DOI:10.3389/fnagi.2021.760270
PMID:34867287
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8634091/
Abstract

Glutamate carboxypeptidase II (GCPII) expression in brain is increased by inflammation, and reduces NAAG (N-acetyl aspartyl glutamate) stimulation of mGluR3 signaling. Genetic insults in this signaling cascade are increasingly linked to cognitive disorders in humans, where increased GCPII and or decreased NAAG-mGluR3 are associated with impaired prefrontal cortical (PFC) activation and cognitive impairment. As aging is associated with increased inflammation and PFC cognitive deficits, the current study examined GCPII and mGluR3 expression in the aging rat medial PFC, and tested whether GCPII inhibition with 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) would improve working memory performance. We found that GCPII protein was expressed on astrocytes and some microglia as expected from previous studies, but was also prominently expressed on neurons, and showed increased levels with advancing age. Systemic administration of the GCPII inhibitor, 2-MPPA, improved working memory performance in young and aged rats, and also improved performance after local infusion into the medial PFC. As GCPII inhibitors are well-tolerated, they may provide an important new direction for treatment of cognitive disorders associated with aging and/or inflammation.

摘要

炎症会使大脑中的谷氨酸羧肽酶II（GCPII）表达增加，从而减少N-乙酰天门冬氨酰谷氨酸（NAAG）对代谢型谷氨酸受体3（mGluR3）信号传导的刺激。该信号级联反应中的基因损伤与人类认知障碍的关联日益紧密，其中GCPII增加和/或NAAG-mGluR3减少与前额叶皮质（PFC）激活受损和认知障碍有关。由于衰老与炎症增加和PFC认知缺陷相关，本研究检测了衰老大鼠内侧PFC中GCPII和mGluR3的表达，并测试了用2-（3-巯基丙基）戊二酸（2-MPPA）抑制GCPII是否能改善工作记忆表现。我们发现，正如先前研究所预期的，GCPII蛋白在星形胶质细胞和一些小胶质细胞上表达，但在神经元上也有显著表达，并且随着年龄增长其水平升高。全身性给予GCPII抑制剂2-MPPA可改善年轻和老年大鼠的工作记忆表现，在内侧PFC局部注射后也能改善表现。由于GCPII抑制剂耐受性良好，它们可能为治疗与衰老和/或炎症相关的认知障碍提供一个重要的新方向。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d627/8634091/bcfefb77a208/fnagi-13-760270-g007.jpg
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