Ml Muscarinic Agonists: From Treatment Toward Delaying Progression of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is characterized, inter alia, by synaptic loss, neurofibrillary tangles, amyloid plaques containing the β-amyloid peptide (Aβ), and degeneration of cholinergic neurons that ascend from the basal forebrain to cortical and hippocampal areas (reviewed by Court and Perry, 1991). A presynaptic cholinergic hypofunction, as one of the major neuronal events in AD, is reflected, inter alia, in reduced levels of acetylcholine (ACh), acetylcholinesterase (AChE) and choline acetyltransferase (ChAT). As a result of neuronal degeneration, the density of presynaptic M2 muscarinic receptors (mAChR) is significantly decreased in AD, yet post-synaptic Ml mAChR are relatively unchanged in AD (review by Court and Perry, 1991) (vide infra for further discussion). Degeneration of cholinergic neurons in AD is presumably a principal cause of the dementia. The “cholinergic hypothesis’.in AD implies that a cholinergic replacement therapy might be beneficial in alleviating some of the cognitive dysfunctions in this disorder (Court and Perry, 1991). Highly selective ml 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. This represents the most relevant approach of cholinergic treatment due to the role of Ml mAChRs in memory and learning processing (Fisher and Barak, 1994, Fisher, 1997). The present overview is an attempt to address some of these findings and to propose an unifying hypotheses regarding ml selective agonists aimed at treatment and therapy of AD.KeywordsNerve Growth FactorMuscarinic ReceptorAmyloid Precursor ProteinSelective AgonistMuscarinic AgonistThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.