Alterations in NMDA receptor subunit densities and ligand binding to glycine recognition sites are associated with chronic anxiety in Alzheimer's disease

Tsang, Shirley W.Y.; Vinters, Harry V.; Cummings, Jeffrey L.; Wong, Peter T.-H.; Chen, Christopher P.L.-H.; Lai, Mitchell K.P.

doi:10.1016/j.neurobiolaging.2007.03.014

« Previous Next »Neurobiology of Aging
Volume 29, Issue 10 , Pages 1524-1532, October 2008

Alterations in NMDA receptor subunit densities and ligand binding to glycine recognition sites are associated with chronic anxiety in Alzheimer's disease

Shirley W.Y. Tsang
- Dementia Research Laboratory, Department of Clinical Research, Singapore General Hospital, Singapore
Harry V. Vinters
- Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Jeffrey L. Cummings
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Peter T.-H. Wong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Christopher P.L.-H. Chen
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Mitchell K.P. Lai
- Dementia Research Laboratory, Department of Clinical Research, Singapore General Hospital, Singapore
- Corresponding author at: Dementia Research Laboratory, Department of Clinical Research, Block 6, Level 6, Room B22, Singapore General Hospital, Outram Road, 169608 Singapore, Singapore. Tel.: +65 6326 6384; fax: +65 6225 7796.

Received 3 November 2006; received in revised form 18 February 2007; accepted 8 March 2007. published online 13 April 2007.

Abstract

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 [³H]MDL105,519 and [³H]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.

Keywords: Alzheimer's disease, Glutamate receptors, Glycine, Neocortex, Anxiety