Reduced retinal function in amyloid precursor protein‐over‐expressing transgenic mice via attenuating glutamate‐N‐methyl‐d‐aspartate receptor signaling

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Abstract
Here, we examined whether amyloid‐β (Aβ) protein participates in cell death and retinal function using three types of transgenic (Tg) mice in vivo [human mutant amyloid precursor protein (APP) Tg (Tg 2576) mice, mutant presenilin‐1 (PS‐1) knock‐in mice, and APP/PS‐1 double Tg mice]. ELISA revealed that the insoluble form of Aβ1‐40 was markedly accumulated in the retinas of APP and APP/PS‐1, but not PS‐1 Tg, mice (vs. wild‐type mice). In APP Tg and APP/PS‐1 Tg mice, immunostaining revealed accumulations of intracellular Aβ1–42 in retinal ganglion cells and in the inner and outer nuclear layers. APP Tg and APP/PS‐1 Tg, but not PS‐1 Tg, mice had less NMDA‐induced retinal damage than wild‐type mice, and the reduced damage in APP/PS‐1 Tg mice was diminished by the pre‐treatment of N‐[N‐(3,5‐difluorophenacetyl)‐l‐alanyl]‐S‐phenylglycine t‐butyl ester, a γ‐secretase inhibitor. Furthermore, the number of TUNEL‐positive cells was significantly less in ganglion cell layer of APP/PS‐1 Tg mice than PS‐1 Tg mice 24 h after NMDA injection. The phosphorylated form of calcium/calmodulin‐dependent protein kinase IIα (CaMKIIα), but not total CaMKIIα or total NMDA receptor 1 (NR1) subunit, in total retinal extracts was decreased in non‐treated retinas of APP/PS‐1 Tg mice (vs. wild‐type mice). CaMKIIα and NR2B proteins, but not NR1, in retinal membrane fraction were significantly decreased in APP/PS‐1 Tg mice as compared with wild‐type mice. The NMDA‐induced increase in p‐CaMKIIα in the retina was also lower in APP/PS‐1 Tg mice than in wild‐type mice. In electroretinogram and visual‐evoked potential recordings, the implicit time to each peak from a light stimulus was prolonged in APP/PS‐1 mice versus wild‐type mice. Hence, Aβ may impair retinal function by reducing activation of NMDA‐receptor signaling pathways.

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