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Cellular and Molecular Life Sciences

, Volume 66, Issue 24, pp 3923–3935 | Cite as

Ectodomain shedding of the receptor for advanced glycation end products: a novel therapeutic target for Alzheimer’s disease

  • Ling ZhangEmail author
  • Rolf Postina
  • Yingqun WangEmail author
Review

Abstract

Receptor for advanced glycation end products (RAGE) mediates diverse physiological and pathological effects and is involved in the pathogenesis of Alzheimer’s disease (AD). RAGE is a receptor for amyloid β peptides (Aβ), mediates Aβ neurotoxicity and also promotes Aβ influx into the brain and contributes to Aβ aggregation. Soluble RAGE (sRAGE), a secreted RAGE isoform, acts as a decoy receptor to antagonize RAGE-mediated damages. Accumulating evidence has suggested that sRAGE represents a promising pharmaceutic against RAGE-mediated disorders. Recent studies revealed proteolysis of RAGE as a previously unappreciated means of sRAGE production. In this review we summarize these findings on the proteolytic cleavage of RAGE and discuss the underlying regulatory mechanisms of RAGE shedding. Furthermore, we propose a model in which proteolysis of RAGE could restrain AD development by reducing Aβ transport into the brain and Aβ production via BACE. Thus, the modulation of RAGE proteolysis provides a novel intervention strategy for AD.

Keywords

Receptor for advanced glycation end products Alzheimer’s disease Ectodomain shedding Amyloid β peptide ADAM10 MMP9 

Notes

Acknowledgments

This work was supported by the Alzheimer Forschung Initiative e.V. (Düsseldorf, Germany) and the Deutsche Forschungsgemeinschaft (DFG Priority Program SPP1085–Cellular Mechanisms of Alzheimer’s Disease). We thank Dr. Zhijun Zhang (Zhongda Hospital Affiliated to Southeast University, Nanjing, China) for support and helpful discussion.

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Copyright information

© Birkhäuser Verlag, Basel/Switzerland 2009

Authors and Affiliations

  1. 1.Department of NeurologyZhongda Hospital Affiliated to Southeast UniversityNanjingChina
  2. 2.Institute of BiochemistryJohannes Gutenberg University of MainzMainzGermany
  3. 3.Abramson Family Cancer Research InstituteUniversity of PennsylvaniaPhiladelphiaUSA

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