Differential inhibition of acetylcholinesterase molecular forms in normal and Alzheimer disease brain

Molecular forms of acetylcholinesterase were studied in three brain regions from Alzheimer disease patients and non-demented, age-matched controls. In Alzheimer disease patients, the membrane-bound G4 form was decreased in frontal (-71%) and parietal cortex (-45%) and in the caudate-putamen (-47%) from control levels. We also found a decrease of aqueous-soluble acetylcholinesterase molecular forms in the aqueous-soluble acetylcholinesterase molecular forms in the caudate-putamen region. The effect of three clinically significant acetylcholinesterase inhibitors, heptyl-physostigmine, physostigmine and edrophonium, on aqueous-soluble acetylcholinesterase molecular forms of the caudate-putamen was investigated. Heptyl-physostigmine, a physostigmine analogue, showed preferential inhibition for the G1 form. On the contrary, edrophonium inhibited the G4 form more potently than the G1 form. Physostigmine inhibited both forms with similar potency. The clinical implications of selective acetylcholinesterase inhibitors are discussed.