Impaired phosphoinositide hydrolysis in Alzheimer's 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 [3H]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 [3H]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.
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham 35294.
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D000368:Aged; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D066298:In Vitro Techniques; D018721:Muscarinic Agonists / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
D018721:Muscarinic Agonists; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002217:Carbachol; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D002118:Calcium