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

There are few studies on the clinical and neurochemical correlates of postsynaptic cholinergic dysfunction in Alzheimerʹs 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.