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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

Citation

Dawkins, E and Gasperini, R and Hu, Y and Cui, H and Vincent, AJ and Bolos, M and Young, KM and Foa, L and Small, DH, 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, Journal of Neuroscience Research, 92, (11) pp. 1478-1489. ISSN 1097-4547 (2014) [Refereed Article]

Copyright Statement

Copyright 2014 Wiley

DOI: doi:10.1002/jnr.23422

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.

Item Details

Item Type:Refereed Article
Keywords:phosphoinositides; lipid; Alzheimer’s disease; amyloid
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Neurosciences not elsewhere classified
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Neurodegenerative Disorders Related to Ageing
Author:Dawkins, E (Dr Edgar Dawkins)
Author:Gasperini, R (Dr Rob Gasperini)
Author:Hu, Y (Ms Ivy Hu)
Author:Cui, H (Mr Hao Cui)
Author:Vincent, AJ (Dr Adele Vincent)
Author:Bolos, M (Dr Marta Bolos Jurado)
Author:Young, KM (Dr Kaylene Young)
Author:Foa, L (Associate Professor Lisa Foa)
Author:Small, DH (Professor David Small)
ID Code:92441
Year Published:2014
Web of Science® Times Cited:3
Deposited By:Menzies Institute for Medical Research
Deposited On:2014-06-18
Last Modified:2015-02-26
Downloads:0

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