Disrupted muscarinic M1 receptor signaling correlates with loss of protein kinase C activity and glutamatergic deficit in Alzheimer's disease.
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 M(1) receptors in the neocortex was associated with dementia severity. The present study aims to study whether this loss of M(1)/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 M(1) receptors, M(1)/G-protein coupling, NMDA receptors as well as protein kinase C (PKC) and Src kinase activities. We found that the extent of M(1)/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 M(1)/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.
Tsang
Shirley W Y
SW
Dementia Research Laboratory, Department of Clinical Research, Singapore General Hospital, Singapore.
Pomakian
Justine
J
Marshall
Gad A
GA
Vinters
Harry V
HV
Cummings
Jeffrey L
JL
Chen
Christopher P L-H
CP
Wong
Peter T-H
PT
Lai
Mitchell K P
MK
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D016022:Case-Control Studies; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D005260:Female; D018698:Glutamic Acid / Q000172:deficiency*; D006801:Humans; D008297:Male; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics; D010890:Pirenzepine / Q000493:pharmacokinetics; D011180:Postmortem Changes; D011493:Protein Kinase C / Q000378:metabolism*; D011869:Radioligand Assay / Q000379:methods; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D010890:Pirenzepine; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D019061:src-Family Kinases; D011493:Protein Kinase C