Tsang Shirley W Y, Vinters Harry V, Cummings Jeffrey L, Wong Peter T-H, Chen Christopher P L-H, Lai Mitchell K P
Dementia Research Laboratory, Department of Clinical Research, Singapore General Hospital, Singapore.
Neurobiol Aging. 2008 Oct;29(10):1524-32. doi: 10.1016/j.neurobiolaging.2007.03.014. Epub 2007 Apr 11.
Glutamatergic deficits are established neuropathological features of Alzheimer's disease (AD) and are known to correlate with cognitive impairments. In contrast, the role of glutamatergic alterations in behavioral and psychological symptoms of dementia (BPSD) is unclear. There is considerable preclinical evidence for the importance of glycine recognition sites (GlyRS) of N-methyl-D-aspartate (NMDA) receptors in the regulation of anxiety behaviors. This study aimed to correlate several glutamatergic measures with chronic anxiety in AD. Twenty-one AD patients assessed by the Neuropsychiatric Inventory (NPI) were divided into low anxiety (LA) and high anxiety (HA) subgroups. GlyRS and NMDA channel were measured by brain homogenate binding with [(3)H]MDL105,519 and [(3)H]MK-801, respectively. Densities of NMDA receptor NR2A, NR2B and alternate spliced NR1 subunits were quantified by immunoblotting. We found that the binding affinity to GlyRS was significantly higher in HA compared to LA, and this higher GlyRS affinity correlated with selective reduction of NR2A density as well as with elevated anxiety scores. Our observations suggest a novel mechanism whereby subunit specific changes in the NMDA receptor complex may be linked to chronic anxiety in AD via effects on GlyRS function. We propose that NR2A and GlyRS should be further assessed as novel targets of behavioral pharmacotherapy in AD.
谷氨酸能缺陷是阿尔茨海默病（AD）已确定的神经病理学特征，并且已知与认知障碍相关。相比之下，谷氨酸能改变在痴呆的行为和心理症状（BPSD）中的作用尚不清楚。有大量临床前证据表明N-甲基-D-天冬氨酸（NMDA）受体的甘氨酸识别位点（GlyRS）在调节焦虑行为中具有重要性。本研究旨在将几种谷氨酸能指标与AD中的慢性焦虑相关联。通过神经精神科问卷（NPI）评估的21名AD患者被分为低焦虑（LA）和高焦虑（HA）亚组。分别通过脑匀浆与[(3)H]MDL105,519和[(3)H]MK-801结合来测量GlyRS和NMDA通道。通过免疫印迹法对NMDA受体NR2A、NR2B和可变剪接的NR1亚基的密度进行定量。我们发现，与LA相比，HA对GlyRS的结合亲和力显著更高，并且这种更高的GlyRS亲和力与NR2A密度的选择性降低以及焦虑评分升高相关。我们的观察结果提示了一种新机制，即NMDA受体复合物中亚基特异性变化可能通过对GlyRS功能的影响与AD中的慢性焦虑相关联。我们建议应进一步评估NR2A和GlyRS作为AD行为药物治疗新靶点的可能性。
