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

Abstract

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 G 4 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 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 G 1 form. On the contrary, edrophonium inhibited the G 4 form more potently than the G 1 form. Physostigmine inhibited both forms with similar potency. The clinical implications of selective acetylcholinesterase inhibitors are discussed.