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Lilla Knels, Claudia Knels, Jana Loeffler, Cornelia Schroeder, Richard Funk, Monika Valtink; Influence of the neuroprotective drug memantine on organ-cultured diabetic or Alzheimer’s disease retina. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1349.
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© ARVO (1962-2015); The Authors (2016-present)
Alzheimer’s disease (AD) is characterized by amyloidogenic processing of the amyloid precursor protein (APP) and subsequent neuronal cell death. Glyoxal induces advanced glycation end products (AGEs) which result in diabetic metabolism. We investigated whether AGEs affect APP processing in the retina, and if the known AD drug memantine can diminish or prevent the formation of AGEs and/or can affect amyloidogenic APP processing via the β-secretase pathway.
AGEs and β-amyloid plaques were induced in retina explants from C57BL/6 (wt) mice by applying 1mmol/l glyoxal. Additionally, retina explants were treated with 10 µmol/l memantine. Retina explants of double transgenic SwAPP/Psen1d9 mice (AD model) were cultured with or without memantine. Explants were analyzed by Western blotting (WB), RT-PCR and immunohistochemistry (IHC), for AD proteins (APP, cleavage products sAPPα/β, β-amyloids, α-/β-secretases), apoptosis and stress markers (AIF, HO-1, Bax, CML), and GFAP after up to 5days cultivation. Explants were further analyzed by ELISA for beta-amyloid production.
Glyoxal increased HO-1 and Bax mRNA levels, but not APP, TACE, BACE, and GFAP mRNA levels, in wt mouse retina. Additional treatment with memantine did not influence APP, TACE, BACE, HO-1, or GFAP, but decreased Bax expression. Memantine could reduce glyoxal-induced AGEs (CML), as seen in WB, while AIF and APP levels remained stable independent of glyoxal or memantine treatment. Glyoxal further induced Amyloid-β 40/42 deposition in the inner nuclear layer (INL) and decreased GFAP levels in Müller cells, as shown by IHC. Memantine could mitigate glyoxal-induced plaque formation in the INL. In the AD model, WB analyzes revealed enhanced APP and β-amyloid levels compared to control (wt) retinas. Here, memantine reduced soluble sAPPβ in retinal culture supernatants. Levels of stress or apoptosis proteins remained unchanged.
Memantine is non-toxic to the retina and might protect cells against glyoxal-induced damage by reducing the formation of AGEs. It may also interfere with the amyloidogenic processing of APP, hence representing a possible medication to prevent retinal damage in AD.
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