Differential Regulation of Molecular Subtypes of Muscarinic Receptors in Alzheimer's Disease

Abstract

Molecular subtypes of muscarinic receptors (m1–m5) are novel targets for cholinergic replacement therapies in Alzheimer's disease. However, the status of these receptors in human brain and Alzheimer's disease is incompletely understood. The m1–m5 receptors in brains from control subjects and Alzheimer's disease patients were examined using a panel of specific antisera and radioligand binding. Quantitative immunoprecipitation demonstrated a predominance of the m1, m2, and m4 receptor subtypes in cortical and subcortical regions in control subjects. In Alzheimer's disease, normal levels of m1 receptors measured by radioligand binding contrasted with decreased m1 receptor immunoreactivity, suggesting that the m1 receptor is altered in Alzheimer's disease. The m2 immunoreactivity was decreased, consistent with the loss of m2 binding sites and the location of this receptor subtype on presynaptic cholinergic terminals. The m4 receptor was up‐regulated significantly and may offer a target for new memory‐enhancing drugs. Differential alterations of molecular subtypes of muscarinic receptors may contribute to the cholinergic component of Alzheimer's disease dementia.

Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia

“…The experimental design of our study does not allow a comparison of relative levels of M1R and M4R protein within BA 9 or BA 40. By contrast, an earlier study using immunoprecipitation of radiolabelled muscarinic receptors with receptor-specific antibodies 23 showed that M1R is the predominant muscarinic receptor in the human cortex. Unfortunately in the immunoprecipitation study, muscarinic receptors were only measured in one cortical region, so it is not possible to compare our results on variations of muscarinic receptors between cortical regions.…”

The Muscarinic M1/M4 Receptor Agonist Xanomeline Exhibits Antipsychotic-Like Activity in Cebus apella Monkeys

“…However, most GABAergic projection neurons in the monkey striatum express either dopamine D 1 or D 2 receptor mRNA (Aubert et al, 2000). Moreover, muscarinic M 4 receptors have been localized in the human striatum (Flynn et al, 1995). In addition, PET studies have shown that [ 11 C]xanomeline binds in the monkey striatum (Farde et al, 1996).…”

Towards a muscarinic hypothesis of schizophrenia

“…[51][52][53][54] All five subtypes of the muscarinic receptors are found in the human CNS, albeit in regionally varying concentrations. 55,56 For example, the basal ganglia and cortex predominantly express M 1 and M 4 receptors, whereas M 2 receptors predominate in the thalamus and brainstem. [57][58][59][60][61] Overall, the M 1 , M 3 and M 4 subtype are found abundantly in the brain, 62 whereas the M 5 -subtype is the least abundant.…”