Biochemical Differentiation of Cholinesterases from Normal and Alzheimers Disease Cortex

Alexis      Ciro; Joon      Park; Gary      Burkhard; Nicole      Yan; Changiz      Geula

Abstract

In Alzheimers disease, histochemically visualized cholinesterases with altered pH optimum for activity and inhibitable by indoleamines and the protease inhibitor bacitracin emerge in association with plaques and tangles. It has been suggested that these cholinesterases may participate in the pathologic process. However, it is not known whether the properties of cholinesterases observed in Alzheimers disease are due to requirements of histochemical procedures or actual biochemical properties of these enzymes. Using biochemical assays of acetylcholinesterase and butyrylcholinesterase activities, we demonstrate here that serotonin and bacitracin result in a significantly greater and dose-dependent inhibition of cholinesterases in Alzheimers disease cortex when compared with age-matched controls. In contrast, variations in pH did not distinguish cholinesterases in Alzheimers disease and control cortex. We also confirmed significant reduction of acetylcholinesterase activity in Alzheimers disease cortex and increased butyrylcholinesterase activity that only approached significance. We conclude that inhibition by indoleamines and bacitracin is a biochemical characteristic of a proportion of cholinesterases in Alzheimers disease that most likely represents the pool associated with plaques and tangles. Most of the available cholinesterase inhibitors are relatively incapable of inhibiting cholinesterases associated with plaques and tangles. The findings of the present investigation open the way for attempts to isolate cholinesterases associated with plaques and tangles and design or discovery of inhibitors specifically targeted to cholinesterases in these lesions

Keywords: Acetylcholinesterase, Alzheimer's disease, butyrylcholinesterase, cholinesterase, cortical cholinergic markers, forebrain cholinergic system, enzymatic inhibition, plaque formation