β‐Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment

EMBO Molecular Medicine

Jun Cai⁶  Xiaoping Qi⁶  Norbert Kociok³  Sergej Skosyrski³  Alonso Emilio⁶  Qing Ruan⁶  Song Han¹  Li Liu⁴  Zhijuan Chen⁶  Catherine Bowes Rickman²  Todd Golde⁸  Maria B. Grant⁴  Paul Saftig⁷  Lutgarde Serneels⁵  Bart de Strooper⁵  Antonia M. Joussen³ 

[1] Department of Surgery, University of Florida, Gainesville, FL, USA;Department of Ophthalmology & of Cell Biology, Duke University Medical Center, Durham, NC, USA;Department of Ophthalmology, Charité Universitätsmedizin Berlin, Berlin, Germany;Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL, USA;Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, Leuven, Belgium;Department of Anatomy & Cell Biology, University of Florida, Gainesville, FL, USA;Biochemical Institute, Christian-Albrecht's University, Kiel, Germany;Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA

关键词: angiogenesis;    β‐secretase;    lipofuscin;    retina;    retinal pigment epithelium;   

DOI  :  10.1002/emmm.201101084

来源: Wiley

【 摘 要 】

Abstract

β-Secretase (BACE1) is a major drug target for combating Alzheimer's disease (AD). Here we show that BACE1^−/− mice develop significant retinal pathology including retinal thinning, apoptosis, reduced retinal vascular density and an increase in the age pigment, lipofuscin. BACE1 expression is highest in the neural retina while BACE2 was greatest in the retinal pigment epithelium (RPE)/choroid. Pigment epithelial-derived factor, a known regulator of γ-secretase, inhibits vascular endothelial growth factor (VEGF)-induced in vitro and in vivo angiogenesis and this is abolished by BACE1 inhibition. Moreover, intravitreal administration of BACE1 inhibitor or BACE1 small interfering RNA (siRNA) increases choroidal neovascularization in mice. BACE1 induces ectodomain shedding of vascular endothelial growth factor receptor 1 (VEGFR1) which is a prerequisite for γ-secretase release of a 100 kDa intracellular domain. The increase in lipofuscin following BACE1 inhibition and RNAI knockdown is associated with lysosomal perturbations. Taken together, our data show that BACE1 plays a critical role in retinal homeostasis and that the use of BACE inhibitors for AD should be viewed with extreme caution as they could lead to retinal pathology and exacerbate conditions such as age-related macular degeneration.

【 授权许可】

CC BY   
Copyright © 2012 EMBO Molecular Medicine

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