Diminished Muscarinic Receptor-stimulated [3H]-PIP2 Hydrolysis in Alzheimer's Disease

The functional integrity of the cortical muscarinic receptor (MR)-mediated phosphatidylinositol 4,5-bisphosphate (PIP2)-specific phospholipase C signalling pathway was assessed in Alzheimer disease (AD) and age-matched control subjects. There was no difference in the basal hydrolysis of [3H]-PIP2 to [3H]-inositol phosphates between control and AD membrane preparations. However, muscarinic agonist-stimulated PIP2 hydrolysis was significantly diminished in the AD cases. Diminished agonist-stimulated PIP2 hydrolysis correlated with the loss in high affinity agonist binding (KL/KH ratio) to the M1 muscarinic receptor subtype in the disease. These data further support the hypothesis that muscarinic receptor-mediated signal transduction is altered in AD, and that the defect lies at the level of muscarinic receptor-G protein/effector coupling.