Research article

Oxysterol-binding protein-1 (OSBP1) modulates processing and trafficking of the amyloid precursor protein

Celina V Zerbinatti^{* 1} , Joanna M Cordy^{* 2} , Ci-Di Chen^{* 3} , Maria Guillily² , Sokreine Suon¹ , William J Ray¹ , Guy R Seabrook¹ , Carmela R Abraham³ and Benjamin Wolozin²

¹Department of Alzheimer's Research, Merck & Co., Inc., West Point, PA, 19486, USA

²Department of Pharmacology, Boston University School of Medicine, Boston, MA, 02118, USA

³Department of Biochemistry, Boston University School of Medicine, Boston, MA, 02118, USA

author email corresponding author email* Contributed equally

Molecular Neurodegeneration 2008, 3:5doi:10.1186/1750-1326-3-5

Published:	18 March 2008

Abstract

Background

Evidence from biochemical, epidemiological and genetic findings indicates that cholesterol levels are linked to amyloid-β (Aβ) production and Alzheimer's disease (AD). Oxysterols, which are cholesterol-derived ligands of the liver X receptors (LXRs) and oxysterol binding proteins, strongly regulate the processing of amyloid precursor protein (APP). Although LXRs have been studied extensively, little is known about the biology of oxysterol binding proteins. Oxysterol-binding protein 1 (OSBP1) is a member of a family of sterol-binding proteins with roles in lipid metabolism, regulation of secretory vesicle generation and signal transduction, and it is thought that these proteins may act as sterol sensors to control a variety of sterol-dependent cellular processes.

Results

We investigated whether OSBP1 was involved in regulating APP processing and found that overexpression of OSBP1 downregulated the amyloidogenic processing of APP, while OSBP1 knockdown had the opposite effect. In addition, we found that OSBP1 altered the trafficking of APP-Notch2 dimers by causing their accumulation in the Golgi, an effect that could be reversed by treating cells with OSBP1 ligand, 25-hydroxycholesterol.

Conclusion

These results suggest that OSBP1 could play a role in linking cholesterol metabolism with intracellular APP trafficking and Aβ production, and more importantly indicate that OSBP1 could provide an alternative target for Aβ-directed therapeutic.