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.
Jope
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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