IMPAIRED PHOSPHOINOSITIDE HYDROLYSIS IN ALZHEIMERS-DISEASE BRAIN

The effect of Alzheimer's disease (AD) on the activity of the phosphoinositide second messenger system was studied by measuring the hydrolysis of [H-3]phosphatidylinositol (PI) by membranes from postmortem human prefrontal cortex. The activity of phospholipase C was similar in AD and control tissue. Activation with GTP gamma S and with carbachol demonstrated less [H-3]PI hydrolysis in AD than control membranes. The concentration of Gq/11, the G-proteins most likely functional in phosphoinositide metabolism, was unchanged in AD compared with controls, indicating that function of the receptor-G-protein complex rather than the G-protein concentration was the site of the impairment in AD. These results indicate that postsynaptic muscarinic receptor responses are impaired in AD, a finding that may explain, in part, the limited therapeutic responses achieved by administration of cholinomimetics to patients with AD. Also, this assay provides a means to identify cholinomimetics that are most effective in activating muscarinic receptor-coupled phosphoinositide hydrolysis in human brain, agents which should have the greatest potential for providing therapeutic responses in AD.