POTENTIAL ROLE OF MUSCARINIC AGONISTS IN ALZHEIMERS-DISEASE

Alzheimer's disease (AD) is a common neurodegenerative disorder and a leading cause of death among the elderly, Recent advances in our under standing of the neurobiology of AD have provided scientific groundwork for the development of potentially more effective and less toxic trea tment strategies for the disease, Some of the neuropathological hallma rks of AD include early and extensive degeneration of cortically proje cting cholinergic neurons in the basal forebrain, and a reduced number of muscarinic acetylcholine receptors, Of note, neocortical muscarini c receptors of the M-1 subtype are relatively preserved in the brains of patients with AD, whereas the presynaptic receptors, which are of t he M-2 subtype, are reduced in number, Therefore, activation of relati vely intact postsynaptic mechanisms by muscarinic M-1 receptor-specifi c agonists could theoretically be more efficacious in the treatment of AD compared with agents (e.g. acetylcholinesterase inhibitors) that p redominantly act on dysfunctional presynaptic terminals. The administr ation of muscarinic agonists can demonstrably enhance cognition and si gnificantly improve some of the disturbing behaviours in patients with AD. Recent advances in our knowledge of the molecular biology of musc arinic receptors, together with a better understanding of signal trans duction pathways in AD, are likely to result in the development of rec eptor-specific muscarinic agonists that are more efficacious and less toxic, Moreover, preliminary evidence concerning the effects of muscar inic agonists on the processing of amyloid precursor protein and the f ormation of neurofibrillary tangles suggests that these agents might f avourably alter the pathobiology of AD.