Possible role of the cholinergic system and disease models

Memory impairment associated with the loss of cortical cholinergic neurons in AD has stimulated the development of animal models based on blockade or destruction of these systems. Strategies include mechanical lesions, local injection of excitotoxic amino acids or ethylcholine aziridinium (AF 64A), which disrupt reference and working memory in rats, but lack specificity for cholinergic systems. Other models involving, reduction in cerebral blood flow and interference with oxidative metabolism of glucose, mimic those found in AD, and also interfere with working and long-term memory in the rat. Memory impairments can be reversed by acetylcholinesterase inhibitors and cholinergic agonists but beneficial effects of these agents in AD patients are small and inconsistent. This may be partly due to unfavorable pharmacokinetics and dose-limiting side effects of existing drugs. Newer, brain specific acetylcholinesterase inhibitors and M1 muscarinic agonists with a lower incidence of unwanted effects are currently being evaluated.