Membrane phospholipid metabolism is abnormal in Alzheimer's disease (AD) brain. Phosphatidylcholine and phosphatidylethanolamine levels are decreased as are choline and ethanolamine, while glycerophosphocholine (GPC) and glycerophosphoethanolamine are increased. (1)To develop a rat model for these changes, we examined the effects of unilateral lesion of the cholinergic nucleus basalis (nBM) with ibotenic acid (10 mg/ml in PBS, 0.5 mu l) and sham lesion on frontocortical phospholipid, choline and GPC. After one week, choline acetyltransferase activity in frontal cortex was decreased (26%, p < 0.005, n = 14) on the nBM ibotenate-lesion side relative to the contralateral side, while there were no differences following the nBM sham-lesion. Levels of membrane phospholipids (nmol/mg protein) in adjacent frontal cortex sections exhibited concomitant decreases (13%, p < 0.05, n = 14) on the nBM ibotenate-lesion side, while there were no differences following the nBM sham-lesion. Tissue nBM ibotenate-lesion frontocortical choline and GPC levels were also decreased relative to those in control tissues (choline: 21%,p < 0.05, n = 14; GPC: 10%, p < 0.05, n = 14), while nBM sham-lesion showed no effect. Muscarinic receptor sensitivity in frontal cortex following nBM ibotenate-lesion was increased, as measured by carbachol-stimulated inositol phosphate production (p < 0.001, n = 12), indicating that increased receptor mediated phospholipid hydrolysis in cortex may occur following nBM ibotenate-lesion. These data suggest that impaired cholinergic transmission alters phospholipid metabolism in cholinergic target regions.
