Loss of M2 Muscarine Receptors in the Cerebral Cortex in Alzheimer's Disease and Experimental Cholinergic Denervation

Abstract

Cerebral cortex samples from patients with Alzheimer's disease and from rats after experimental cholinergic denervation of the cerebral cortex exhibited reductions in the presynaptic marker choline acetyltransferase activity and in the number of M2 muscarine receptors, with no change in the number of M1 receptors. These results are in keeping with evidence that M2 receptors function in cholinergic nerve terminals to regulate the release of acetylcholine, whereas M1 receptors are located on postsynaptic cells and facilitate cellular excitation. New M1-selective agonists and M2-selective antagonists directed at post- or presynaptic sites deserve consideration as potential agents for the treatment of the disease.

Donepezil effects on sources of cortical rhythms in mild Alzheimer's disease: Responders vs. Non-Responders

“…A similar situation is encountered in AD, a disease deeply affecting the cholinergic basal forebrain (Rodriguez et al, 1999a,b;Dierks et al, 1993Dierks et al, , 2000Huang et al, 2000;Mesulam, 2004;Mesulam et al, 2004). In this framework, AD would be not characterized by a diffuse impairment of the cholinergic systems since brainstem cholinergic innervation of the thalamus was relatively spared (Mash et al, 1985;Geula and Mesulam, 1989Mesulam, 2004). Finally, it has been recently demonstrated that the cholinergic basal forebrain is more structurally impaired in AD patients who respond to cholinergic therapy as compared to Non-Responders .…”

Antisense ‘knockdowns’ of M1 receptors induces transient anterograde amnesia in mice

“…Morphological and neurochemical studies of Alzheimer's disease, the major type of dementia, revealed marked decreases in the cholinergic innervation of the cortex and hippocampus (Bartus et al, 1982;Mash et al, 1985;Whitehouse, 1986). Drugs involving cholinergic stimulation alleviated cognitive dysfunctions in Alzheimer's disease (Bartus et al, 1982) and in particular M 1 -selective agonists have been proposed as a promising treatment strategy in this pathology (Mash et al, 1985;Whitehouse, 1986;Fisher et al, 1989;Gualtieri et al, 1995). On the other hand, cholinergic blockade produces significant impairments of cognitive functions.…”

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

“…In fact, M2 mAChR are progressively decreased in AD. 64 Therefore, it can be postulated that the effects of such M2 antagonists may be transient, as the approach is entirely dependent on enhanced release of presynaptic ACh, which is diminished as a result of a progressive presynaptic cholinergic hypofunction in AD. In this regard, the M2 antagonists may not offer a significant advantage versus the already prescribed AChE-Is in AD patients.…”