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

Jun Cai, Xiaoping Qi, Norbert Kociok, Sergej Skosyrski, Alonso Emilio, Qing Ruan, Song Han, Li Liu, Zhijuan Chen, Catherine Bowes Rickman, Todd Golde, Maria B. Grant, Paul Saftig, Lutgarde Serneels, Bart de Strooper, Antonia M. Joussen, Michael E. Boulton

Research output: Contribution to journalArticle

87 Citations (Scopus)

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 100kDa 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.

Original languageEnglish (US)
Pages (from-to)980-991
Number of pages12
JournalEMBO Molecular Medicine
Volume4
Issue number9
DOIs
StatePublished - Sep 2012
Externally publishedYes

Fingerprint

Retinal Vessels
Amyloid Precursor Protein Secretases
Lipofuscin
Pathology
Alzheimer Disease
Vascular Endothelial Growth Factor Receptor-1
Choroidal Neovascularization
Choroid
Retinal Pigment Epithelium
Macular Degeneration
Vascular Endothelial Growth Factor A
Small Interfering RNA
Retina
Homeostasis
Apoptosis
Pharmaceutical Preparations
Inhibition (Psychology)

Keywords

  • β-secretase
  • Angiogenesis
  • Lipofuscin
  • Retina
  • Retinal pigment epithelium

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. / Cai, Jun; Qi, Xiaoping; Kociok, Norbert; Skosyrski, Sergej; Emilio, Alonso; Ruan, Qing; Han, Song; Liu, Li; Chen, Zhijuan; Bowes Rickman, Catherine; Golde, Todd; Grant, Maria B.; Saftig, Paul; Serneels, Lutgarde; de Strooper, Bart; Joussen, Antonia M.; Boulton, Michael E.

In: EMBO Molecular Medicine, Vol. 4, No. 9, 09.2012, p. 980-991.

Research output: Contribution to journalArticle

Cai, J, Qi, X, Kociok, N, Skosyrski, S, Emilio, A, Ruan, Q, Han, S, Liu, L, Chen, Z, Bowes Rickman, C, Golde, T, Grant, MB, Saftig, P, Serneels, L, de Strooper, B, Joussen, AM & Boulton, ME 2012, 'β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment', EMBO Molecular Medicine, vol. 4, no. 9, pp. 980-991. https://doi.org/10.1002/emmm.201101084
Cai, Jun ; Qi, Xiaoping ; Kociok, Norbert ; Skosyrski, Sergej ; Emilio, Alonso ; Ruan, Qing ; Han, Song ; Liu, Li ; Chen, Zhijuan ; Bowes Rickman, Catherine ; Golde, Todd ; Grant, Maria B. ; Saftig, Paul ; Serneels, Lutgarde ; de Strooper, Bart ; Joussen, Antonia M. ; Boulton, Michael E. / β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. In: EMBO Molecular Medicine. 2012 ; Vol. 4, No. 9. pp. 980-991.
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AU - Liu, Li

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AU - Saftig, Paul

AU - Serneels, Lutgarde

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