title: The N-terminal fragment of the β-amyloid precursor protein of Alzheimer's disease (N-APP) binds to phosphoinositide-rich domains on the surface of hippocampal neurons.
abstract: The function of the β-amyloid precursor protein (APP) of Alzheimer's disease is poorly understood. The secreted ectodomain fragment of APP (sAPPα) can be readily cleaved to produce a small N-terminal fragment (N-APP) that contains heparin-binding and metal-binding domains and that has been found to have biological activity. In the present study, we examined whether N-APP can bind to lipids. We found that N-APP binds selectively to phosphoinositides (PIPs) but poorly to most other lipids. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 )-rich microdomains were identified on the extracellular surface of neurons and glia in primary hippocampal cultures. N-APP bound to neurons and colocalized with PIPs on the cell surface. Furthermore, the binding of N-APP to neurons increased the level of cell-surface PI(4,5)P2 and phosphatidylinositol 3,4,5-trisphosphate. However, PIPs were not the principal cell-surface binding site for N-APP, because N-APP binding to neurons was not inhibited by a short-acyl-chain PIP analogue, and N-APP did not bind to glial cells which also possessed PI(4,5)P2 on the cell surface. The data are explained by a model in which N-APP binds to two distinct components on neurons, one of which is an unidentified receptor and the second of which is a PIP lipid, which binds more weakly to a distinct site within N-APP. Our data provide further support for the idea that N-APP may be an important mediator of APP's biological activity.
authors.affiliation: Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Edgar
authors.initials: E
authors.lastname: Dawkins
authors.forename: Robert
authors.initials: R
authors.lastname: Gasperini
authors.forename: Yanling
authors.initials: Y
authors.lastname: Hu
authors.forename: Hao
authors.initials: H
authors.lastname: Cui
authors.forename: Adele J
authors.initials: AJ
authors.lastname: Vincent
authors.forename: Marta
authors.initials: M
authors.lastname: Bolós
authors.forename: Kaylene M
authors.initials: KM
authors.lastname: Young
authors.forename: Lisa
authors.initials: L
authors.lastname: Foa
authors.forename: David H
authors.initials: DH
authors.lastname: Small
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; C106336:phosphatidylinositol 3,5-diphosphate
keywords: Alzheimer's disease; amyloid; lipid; phosphoinositides