Glutamate Carboxypeptidase II in Aging Rat Prefrontal Cortex Impairs Working Memory Performance.
Glutamate Carboxypeptidase II in Aging Rat Prefrontal Cortex Impairs Working Memory Performance.
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DOI：
10.3389/fnagi.2021.760270
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发表时间：
2021
影响因子：
4.8
通讯作者：
Arnsten AFT
中科院分区：
文献类型：
--
作者：
Datta D;Leslie SN;Woo E;Amancharla N;Elmansy A;Lepe M;Mecca AP;Slusher BS;Nairn AC;Arnsten AFT
谷氨酸羧肽酶II（GCPII）在脑中的表达因炎症而增加，并减少NAAG（N-乙酰基谷氨酸）对mGluR 3信号传导的刺激。这种信号级联中的遗传损伤越来越多地与人类的认知障碍相关，其中GCPII增加和/或NAAG-mGluR 3减少与受损的前额叶皮质（PFC）激活和认知障碍相关。由于衰老与炎症增加和PFC认知缺陷相关，因此本研究检测了衰老大鼠内侧PFC中的GCPII和mGluR 3表达，并测试了2-（3-巯基丙基）戊二酸（2-MPPA）抑制GCPII是否会改善工作记忆表现。我们发现，GCPII蛋白表达的星形胶质细胞和一些小胶质细胞的预期从以前的研究，但也显着表达的神经元，并显示随着年龄的增长而增加的水平。GCPII抑制剂，2-MPPA，全身给药，改善年轻和老年大鼠的工作记忆性能，并改善性能后，局部输注到内侧PFC。由于GCPII抑制剂是耐受性良好，他们可能会提供一个重要的新的方向与衰老和/或炎症相关的认知障碍的治疗。
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.
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影响因子：
10.6
作者：
Dogra S;Stansley BJ;Xiang Z;Qian W;Gogliotti RG;Nicoletti F;Lindsley CW;Niswender CM;Joffe ME;Conn PJ
通讯作者：
Conn PJ
影响因子：
--
作者：
Canetta S;Teboul E;Holt E;Bolkan SS;Padilla-Coreano N;Gordon JA;Harrison NL;Kellendonk C
通讯作者：
Kellendonk C
DOI：
10.1176/appi.ajp.2009.08091445
发表时间：
2009-07
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Ghose S;Gleason KA;Potts BW;Lewis-Amezcua K;Tamminga CA
通讯作者：
Tamminga CA
DOI：
10.1002/alz.12325
发表时间：
2021-06
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Datta D;Leslie SN;Wang M;Morozov YM;Yang S;Mentone S;Zeiss C;Duque A;Rakic P;Horvath TL;van Dyck CH;Nairn AC;Arnsten AFT
通讯作者：
Arnsten AFT
影响因子：
2.8
作者：
Huang, XM;Bennett, M;Thorpe, PE
通讯作者：
Thorpe, PE