title: Effects of Abeta1-42 fibrils and of the tetrapeptide Pr-IIGL on the phosphorylation state of the tau-protein and on the alpha7 nicotinic acetylcholine receptor in vitro.
abstract: In order to investigate the possible links connecting beta-amyloid (Abeta) accumulation, tau-hyperphosphorylation and nicotinic receptor expression, rat embryonic primary hippocampal cultures were incubated with amyloidogenic peptides. Exposure to 0.5 microm fibrillar Abeta(1-42) for 3 days caused retraction of dendrites, shrinkage of cell bodies and a decrease in the expression of microtubule-associated proteins 2b (MAP2b), without affecting the total number of neurons and their viability. No impact on the tau-phosphorylation sites Ser-202, Thr231/Ser235, Ser262 and Ser396/Ser404 was found. The total number of homomeric alpha7-nicotinic receptors (alpha7-nAChRs) and their affinity for [(125)I]alpha-bungarotoxin remained unaltered. Upon incubation with the putatively protective tetrapeptide propionyl-isoleucine-isoleucine-glycine-leucine (Pr-IIGL), an analogue of the region [31-34] of Abeta, cell bodies were swollen in the region of the apical dendrite. These morphological alterations, different from those elicited by Abeta(1-42), did not involve MAP2 expression changes. In contrast to Abeta(1-42), Pr-IIGL caused a massive hyperphosphorylation of the tau-protein at Ser-202 and at Ser396/Ser404. The total number of homomeric alpha7-nAChRs and their affinity for [(125)I]alpha-bungarotoxin were unaffected. In conclusion, the present results show a toxic effect of Abeta(1-42) on the cytoskeletal structure at concentrations normally present in the brains of Alzheimer's disease patients, but raise some doubts about the role of Abeta(1-42) fibrils as a direct trigger of tau-hyperphosphorylation. The tetrapeptide Pr-IIGL cannot be considered protective with regard to cell morphology. Although it prevents the Abeta(1-42)-induced retraction of dendrites, it exhibits other toxic properties. The homomeric alpha7-nAChRs were not affected either by Abeta(1-42) incubation or by Pr-IIGL-induced tau-hyperphosphorylation.
authors.affiliation: Department II of Anatomy - Neuroanatomy, University of Cologne, Joseph Stelzmann-Strasse 9, 50931 Cologne, Germany.
authors.forename: Enzo
authors.initials: E
authors.lastname: Lain
authors.forename: Botond
authors.initials: B
authors.lastname: Penke
authors.forename: André
authors.initials: A
authors.lastname: Delacourte
authors.forename: Daniela
authors.initials: D
authors.lastname: Gündisch
authors.forename: Hannsjörg
authors.initials: H
authors.lastname: Schröder
authors.forename: Brigitte
authors.initials: B
authors.lastname: Witter
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000648:ultrastructure; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002038:Bungarotoxins / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D004622:Embryo, Mammalian; D000939:Epitopes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D007150:Immunohistochemistry / Q000379:methods; D007456:Iodine Isotopes / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002038:Bungarotoxins; D000939:Epitopes; D007456:Iodine Isotopes; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; C075222:amyloid beta-protein (1-42); C106796:propionyl-isoleucyl-isoleucyl-glycyl-leucinamide; D016875:tau Proteins; D012694:Serine