April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Influence of a tripartite BACE1 inhibitor on retina in an Alzheimer's disease mouse model
Author Affiliations & Notes
  • Jana Loeffler
    Medical faculty, TU Dresden, Department of Anatomy, Dresden, Germany
  • Felix Karich
    Medical faculty, TU Dresden, Department of Anatomy, Dresden, Germany
  • Claudia Knels
    Medical faculty, TU Dresden, Department of Anatomy, Dresden, Germany
  • Monika Valtink
    Medical faculty, TU Dresden, Department of Anatomy, Dresden, Germany
  • Hans-Joachim Knölker
    TU Dresden, Department of Chemistry, Dresden, Germany
  • Richard Funk
    Medical faculty, TU Dresden, Department of Anatomy, Dresden, Germany
    CRTD Center for Regenerative Therapies, Dresden, Germany
  • Cornelia Schroeder
    Medical faculty, TU Dresden, Department of Anatomy, Dresden, Germany
    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
  • Lilla Knels
    Medical faculty, TU Dresden, Department of Anatomy, Dresden, Germany
  • Footnotes
    Commercial Relationships Jana Loeffler, None; Felix Karich, None; Claudia Knels, None; Monika Valtink, None; Hans-Joachim Knölker, None; Richard Funk, None; Cornelia Schroeder, None; Lilla Knels, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 1339. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Jana Loeffler, Felix Karich, Claudia Knels, Monika Valtink, Hans-Joachim Knölker, Richard Funk, Cornelia Schroeder, Lilla Knels, ; Influence of a tripartite BACE1 inhibitor on retina in an Alzheimer's disease mouse model. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1339.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose: In Alzheimer’s disease (AD) characteristic amyloid plaques accumulate in the retina and brain, leading to neurodegeneration in both tissues. Pathologic amyloid proteins accumulate earlier in retina than in brain. To interfere with retinal beta-amyloid formation and deposition, we investigated the ability of Tri-01, a hydrophobic tripartite lipid raft-targeted transition state inhibitor of BACE1 (Rajendran et al. Science 320: 520-523).

Methods: Retinal explants from adult double transgenic SwAPP/Psen1d9 mice (AD model) and wild-type C57BL/6 mice (healthy wt controls) were cultured with 1µmol/l Tri-01. Explants were analyzed by Western blotting, ELISA and immunohistochemistry for characteristic AD proteins (APP, amyloid beta, APP cleavage products sAPP-alpha and sAPP-beta), and for apoptosis and stress markers. Furthermore, 1µmol/l of a rhodamine-labeled inhibitor variant, Tri-02, was tested on retinal explants for 1-5 days. In order to gauge retinal uptake in vivo Tri-02 was intravitreally injected and analyzed in cryosections. As an alternative, liposomal eye drops were investigated.

Results: Retina explants from AD mice (SwAPP/Psen1d9) exhibited enhanced APP production with increased amyloid processing and beta-amyloid plaque accumulation compared to wt mice. In AD retina, treatment with Tri-01 decreased levels of soluble sAPP-beta and of amyloid beta 40/42 after 3-5 days. Apoptosis and cell stress marker levels remained unchanged irrespective of drug treatment. Thus, Tri-01 proved non-toxic to retinal tissue at the applied concentration. A single dose of Tri-02 in culture explants showed that about 600nmol/l remained in the retina after 5 days, while most of the substance accumulated on the filter membrane. After intravitreal injection, Tri-02 was detected in all retinal layers, especially in photoreceptor outer segments, and remained retina-associated. Liposomal eye drops could not permeate the cornea and sclera, and had no effect on the retina.

Conclusions: Retinal explant culture is a useful in vitro-model for investigating the mechanism and treatment of AD retinopathy. Tri-01 is an effective protective agent against amyloid-induced retinal degeneration in vitro and, with its long half-life, is a promising candidate for preclinical testing. The retina is accessible for treating local amyloid pathology and, due to easy in vivo-monitoring, also for controlling systemic AD treatment in vivo.

Keywords: 695 retinal degenerations: cell biology • 690 retina: neurochemistry • 503 drug toxicity/drug effects  
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×