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