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The N ‐terminal fragment of the β‐amyloid precursor protein of A lzheimer's disease ( N‐APP ) binds to phosphoinositide‐rich domains on the surface of hippocampal neurons
Author(s) -
Dawkins Edgar,
Gasperini Robert,
Hu Yanling,
Cui Hao,
Vincent Adele J.,
Bolós Marta,
Young Kaylene M.,
Foa Lisa,
Small David H.
Publication year - 2014
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.23422
Subject(s) - ectodomain , amyloid precursor protein , hippocampal formation , binding site , phosphatidylinositol , microbiology and biotechnology , chemistry , receptor , biochemistry , biology , alzheimer's disease , neuroscience , signal transduction , medicine , disease , pathology
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)P 2 )‐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)P 2 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)P 2 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. © 2014 Wiley Periodicals, Inc.