Muscarinic receptor subtype distribution in the central nervous system and relevance to aging and Alzheimer's disease

Abstract

Muscarinic acetylcholine receptors (mAChRs) are G proteincoupled receptors (GPCRs) that mediate the metabotropic actions of acetylcholine (ACh). There are five subtypes of mAChR, M1 - M5, which are expressed throughout the central nervous system (CNS) on numerous cell types and represent promising treatment targets for a number of different diseases, disorders, and conditions of the CNS. Although the present review will focus on Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), a number of conditions such as Parkinson's disease (PD), schizophrenia, and others represent significant unmet medical needs for which selective muscarinic agents could offer therapeutic benefits. Numerous advances have been made regarding mAChR localization through the use of subtype-selective antibodies and radioligand binding studies and these efforts have helped propel a number of mAChR therapeutics into clinical trials. However, much of what we know about mAChR localization in the healthy and diseased brain has come from studies employing radioligand binding with relatively modest selectivity. The development of subtype-selective small molecule radioligands suitable for in vitro and in vivo use, as well as robust, commercially-available antibodies remains a critical need for the field. Additionally, novel genetic tools should be developed and leveraged to help move the field increasingly towards a systems-level understanding of mAChR subtype action. Finally, functional, proteomic, and genetic data from ongoing human studies hold great promise for optimizing the design and interpretation of studies examining receptor levels by enabling patient stratification. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'.