Disrupted muscarinic M1 receptor signaling correlates with loss of protein kinase C activity and glutamatergic deficit in Alzheimer's disease

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

doi:10.1016/j.neurobiolaging.2006.06.001

« Previous Next »Neurobiology of Aging
Volume 28, Issue 9 , Pages 1381-1387, September 2007

Disrupted muscarinic M₁ receptor signaling correlates with loss of protein kinase C activity and glutamatergic deficit in Alzheimer's disease

Shirley W.Y. Tsang
- Dementia Research Laboratory, Department of Clinical Research, Singapore General Hospital, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Justine Pomakian
- Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Gad A. Marshall
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Harry V. Vinters
- Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Jeffrey L. Cummings
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Christopher P.L.-H. Chen
- Department of Neurology, National Neuroscience Institute, Singapore
Peter T.-H. Wong
- 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
- Correspondence to: Dementia Research Laboratory, Department of Clinical Research, Block 6, Level 6, Room B22, Singapore General Hospital, Outram Road, Singapore 169608, Singapore. Tel.: +65 6321 3731; fax: +65 6225 7796.

Received 2 March 2006; received in revised form 8 April 2006; accepted 2 June 2006. published online 10 July 2006.

Abstract

There are few studies on the clinical and neurochemical correlates of postsynaptic cholinergic dysfunction in Alzheimer's disease (AD). We have previously found that attenuation of guanine nucleotide-binding (G-) protein coupling to muscarinic M₁ receptors in the neocortex was associated with dementia severity. The present study aims to study whether this loss of M₁/G-protein coupling is related to alterations in signaling kinases and NMDA receptors. Postmortem frontal cortices of 22 AD subjects and 12 elderly controls were obtained to measure M₁ receptors, M₁/G-protein coupling, NMDA receptors as well as protein kinase C (PKC) and Src kinase activities. We found that the extent of M₁/G-protein coupling loss was correlated with reductions in PKC activity and NMDA receptor density. In contrast, Src kinase activity was neither altered nor associated with M₁/G-protein coupling. Given the well established roles of neuronal PKC signaling and NMDA receptor function in cognitive processes, our results lend further insight into the mechanisms by which postsynaptic cholinergic dysfunction may underlie the cognitive features of AD, and suggest alternative therapeutic targets to cholinergic replacement.

Keywords: Muscarinic receptors, Glutamate receptors, Protein kinase C, Src kinase, Neocortex