INHIBITOR OF ANTAGONIST BINDING TO THE MUSCARINIC RECEPTOR IS ELEVATED IN ALZHEIMERS BRAIN

The 100,000 x g supernatant fraction of human brain contains endogenou s inhibitors of antagonist binding to the muscarinic receptor. Signifi cantly greater inhibition was observed with Alzheimer's than non-demen ted control supernatant fractions. Low molecular weight inhibitor was separated from larger inhibitor species by membrane dialysis (3,500 da lton cut-off). The activity of low molecular weight inhibitor was grea tly increased by sulfhydryl reducing agents. While the low molecular w eight inhibitor was stable to heat, acid and base for short lime perio ds (< 20 min), it was inactivated by acid hydrolysis (50% loss after 1 6 h, 100% loss after 96 h). The low molecular weight inhibitor activit y is elevated approximately three-fold in Alzheimer's brain. The low m olecular weight inhibitor from Alzheimer's brain was found to be a non -competitive inhibitor. This is the first report of endogenous inhibit ors in human brain of ligand binding to the muscarinic receptor and of increased inhibitor activity in Alzheimer's disease.