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Jana Löffler, Felix Karich, Monika Valtink, Richard Funk, Lilla Knels; Retinal Amyloid Precursor Protein (APP) processing and amyloid-beta (Aβ) transport in an Alzheimer’s disease (AD) mouse model. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2270.
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© 2017 Association for Research in Vision and Ophthalmology.
Aβ plaque accumulation and consequential neurodegeneration is observed in the retina in AD, but also in retinal diseases like diabetic retinopathy or wet age-related macular degeneration. Retinal AD manifestation might be prevented by 1) inhibiting Aβ accumulation, or 2) fostering elimination of Aβ. Addressing both, we applied intravitreally a beta secretase (BACE) inhibitor in an AD mouse model (SwAPP/Psen1d9), and investigated possible clearance pathways for Aβ.
The BACE inhibitor Tri-01 (100µmol/l, 1µl) was intravitreally injected 2x (day 0 and day 4) in adult SwAPP/Psen1d9 mice (control: contralateral vehicle only injection). After 8 days retina samples of adult SwAPP/Psen1d9 and wild-type C57BL/6 mice (healthy wt controls) were embedded in paraffin or were lysed for protein analyses. APP and its cleavage products Aβ 40/42, sAPPα and sAPPβ were immunostained in retinal sections, and quantified in retinal lysates by western blotting and ELISA. Brain and retina sections and retinal whole-mounts of non-injected animals were also immunostained for Aβ 40/42 in combination with podoplanin (lymphatic vessel marker), or low density lipoprotein receptor-related protein 1 (LRP-1, involved in Aβ clearance in the brain), and IDE (insulin degrading enzyme, involved in Aβ cleavage) in brain sections. Plaque number and size were analyzed with Fiji software.
AD mice retinas exhibited enhanced APP production with increased amyloid processing and Aβ accumulation vs. wt mice. Retinal Aβ plaques were much smaller than in brain. Aβ was located around and in blood vessels, suggesting a cerebral amyloid angiopathy in this model. Intravitreal injection of Tri-01 decreased sAPPβ and APP staining in the inner retina and significantly reduced the APP cleavage product CTFβ (p=0,03). Podoplanin co-localized with Aβ and was increased in AD retinas vs. wt, indicating lymphatic-like vessels in the retina. LRP-1 co-localized with plaques in inner retinal layers. IDE localized to the hippocampal cortex.
Aβ reduction by intravitreal application of Tri-01 presents a therapeutical option for Aβ associated retinal diseases. Aβ clearance from the retina may occur via lymphatic structures similar to the glymphatic system in the brain. These structures appear enhanced in AD. Involvement of IDE in retinal Aβ clearance remains to be investigated.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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