Muscarinic agonists for the treatment of Alzheimer's disease: progress and perspectives

Much interest has focused on the development of selective muscarinic agonists for the treatment of Alzheimer's disease (AD). Cholinergic replacement therapy is thought to be beneficial in alleviating some of the cognitive dysfunctions in this disorder. The cholinergic neuronal tracts are involved in memory and learning processes, and the extent of the degeneration of the cortical projections correlates with the severity of the dementia. An M1 selective muscarinic agonist may be effective in treating at least some of the cognitive symptoms in AD. Highly selective M1 agonists, producing cellular excitation, should be beneficial in AD, regardless of the extent of degeneration of presynaptic cholinergic projections to the frontal cortex or hippocampus. Functional abnormalities in AD may also occur along various signal transduction pathways mediated, in part, at least, by muscarinic receptors. In general, activities associated with mAChR subtypes and m1 receptors, in particular, indicate that M1 agonists may also be useful for this aspect of AD. Mismetabolism of amyloid precursor proteins (APPs) may induce AD. Recent studies indicate that the formation of the b-amyloid peptide (Abeta) and amyloid plaques is linked to the loss of cholinergic function in AD. New data on the activation of m1 mAChRs in conjunction with recent findings that the induction of such receptors stimulates neurotrophic-like activities, decreases tau phosphorylation and inhibits apoptosis indicate that restoring the cholinergic tone in AD may be useful both in improving memory function and in altering the onset and progression of AD dementia. This article focuses on the recent, promising developments in this field and assesses the value of muscarinic agonists currently under development for the treatment of AD.