Apolipoprotein E isoform-specific disruption of phosphoinositide hydrolysis:: protection by estrogen and glutathione

The mechanism(s) by which the E4 isoform of apolipoprotein E (apoE4) influences Alzheimer's disease (AD) are not fully known. We report that apoE4, but not apoE3, disrupts carbachol-stimulated phosphoinositide (PI) hydrolysis in SH-SY5Y neuroblastoma cells. Carbachol responses were also disrupted by beta -amyloid (A beta) (1-42) and apoE4/A beta (1-42) complexes, but not by apoE3/A beta (1-42). Glutathione and estrogen protected against apoE4 and AP(1-42) effects, as wen as those Of H2O2. Estrogen protection was partially blocked by wortmannin, suggesting the involvement of phosphatidylinositol 3-kinase. An apoE4-induced disruption of acetylcholine muscarinic receptor-mediated signalling may explain the lower effectiveness of cholinergic replacement treatments in apoE4 AD patients. Also, the beneficial effect of estrogen in AD may be partially due to its ability to protect against apoE4- and A beta (142)-mediated disruption of PI hydrolysis. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.