title: Apolipoprotein E isoform-specific disruption of phosphoinositide hydrolysis: protection by estrogen and glutathione.
abstract: 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 (Abeta) (1-42) and apoE4/Abeta(1-42) complexes, but not by apoE3/Abeta(1-42). Glutathione and estrogen protected against apoE4 and Abeta(1-42) effects, as well as those of H(2)O(2). 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 Abeta(1-42)-mediated disruption of PI hydrolysis.
authors.affiliation: Karolinska Institutet, NEUROTEC, Division of Experimental Geriatrics, NOVUM, KFC, 141 86, Huddinge, Sweden. angel.cedazo-minguez@neurotec.ki.se
authors.forename: A
authors.initials: A
authors.lastname: Cedazo-Mínguez
authors.forename: R F
authors.initials: RF
authors.lastname: Cowburn
mesh_terms: D001057:Apolipoproteins E / Q000502:physiology*; D004967:Estrogens / Q000502:physiology*; D005978:Glutathione / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D010716:Phosphatidylinositols / Q000378:metabolism*; D020033:Protein Isoforms / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D001057:Apolipoproteins E; D004967:Estrogens; D010716:Phosphatidylinositols; D020033:Protein Isoforms; D005978:Glutathione