Experimental pharmacology of Alzheimer disease.
Evidence for a major role of acetylcholine in the pathogenesis of AD is provided by the dramatic decrease in the hippocampus and frontal cortex of choline acetyltransferase and the marked reduction in cholinergic neuron counts in the nucleus basalis in post-mortem studies of AD brains. The ChAT deficit correlates with histopathologic changes and psychologic test scores. Pharmacologic mimicking by anti-cholinergics of the core symptoms of AD, and modest enhancement of memory and cognition by cholinomimetic agents support a cholinergic-deficit theory in AD. These findings strongly support therapeutic cholinergic strategies. A presynaptic approach utilizing acetylcholine precursors alone has been discouraging; however, precursor loading coupled with an agent that accelerates acetylcholine release shows promise. At the synaptic level, improvement in the encoding of new information into long-term memory in AD during parenteral administration of acetylcholinesterase inhibitors should enable psychopharmacologists to focus on the development of practical chronic oral treatments. Postsynaptic cholinergic receptor agonists bypass the degenerating presynaptic cholinergic neuron and increase cholinergic neurotransmission at the intact muscarinic receptor. Trials evaluating the effects of cholinergic neuromodulators on cognition provide another tactic in the fight against the disabling consequences of this disorder.
D000109:Acetylcholine / Q000378:metabolism; D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy*; D003704:Dementia / Q000188:drug therapy*; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism; D010095:Oxotremorine / Q000627:therapeutic use; D010455:Peptides / Q000378:metabolism; D010830:Physostigmine / Q000627:therapeutic use; D011950:Receptors, Cholinergic / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013004:Somatostatin / Q000627:therapeutic use; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D010455:Peptides; D011950:Receptors, Cholinergic; D012701:Serotonin; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D010095:Oxotremorine; D010830:Physostigmine; D000109:Acetylcholine; D004298:Dopamine; D009638:Norepinephrine