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Impaired phosphoinositide hydrolysis in Alzheimer's disease brain.

Abstract
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.
AuthorsR S Jope, L Song, X Li, R Powers
JournalNeurobiology of aging (Neurobiol Aging) 1994 Mar-Apr Vol. 15 Issue 2 Pg. 221-6 ISSN: 0197-4580 [Print] United States
PMID7838295 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Muscarinic Agonists
  • Phosphatidylinositols
  • Receptors, Muscarinic
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Carbachol
  • Type C Phospholipases
  • GTP-Binding Proteins
  • Calcium
Topics
  • Aged
  • Alzheimer Disease (enzymology, metabolism)
  • Blotting, Western
  • Brain Chemistry (drug effects, physiology)
  • Calcium (metabolism)
  • Carbachol (pharmacology)
  • GTP-Binding Proteins (metabolism)
  • Guanosine 5'-O-(3-Thiotriphosphate) (metabolism)
  • Humans
  • Hydrogen-Ion Concentration
  • Hydrolysis
  • In Vitro Techniques
  • Muscarinic Agonists (pharmacology)
  • Phosphatidylinositols (metabolism)
  • Receptors, Muscarinic (drug effects, metabolism)
  • Type C Phospholipases (metabolism)

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