Involvement of Amyloid-ß in Retinal Function

Abstract

Purpose:: To clarify whether amyloid-ß (Aß) protein participated in retinal function and cell death using three types of transgenic (Tg) mice: human mutant amyloid precursor protein (APP) Tg (Tg 2576), mutant presenilin-1 (PS-1) knockin, and APP/PS-1 double Tg mice.

Methods:: APP and Aß proteins in retinal extracts or specimens were determined with an ELISA assay or immunostaining. Retinal damage was induced by intravitreal injection of N-methyl-d-aspartate (NMDA) at 5 nmol. NMDA receptor 1 (NR1) subunit and phosphorylated form (Thr286) of calcium/calmodulin-dependent protein kinase IIα (p-CaMKIIα) were measured in retinal extracts and specimens using an immunoblotting and immunostaining. Electroretinogram (ERG) was recorded from APP/PS-1 Tg and their wild-type mice.

Results:: Insoluble form of Aß_1-40 was significantly increased in retina of APP and APP/PS-1, but not PS-1 Tg mice, as compared with that of their wild-type mice. Immunostaining revealed the accumulation of intracellular Aß_1-42 in retinal ganglion cells, inner nuclear layer and outer nuclear layer of APP Tg mice and APP/PS-1 Tg mice. Interestingly, APP and APP/PS-1 Tg mice, but not PS-1 Tg mice, had smaller NMDA-induced retinal damage than their wild-type mice, although there were no histological differences in non-treated retina between each Tg mice and wild-type mice. P-CaMKIIα, but not total CaMKIIα or total NR1, was decreased in non-treated retinas of APP/PS-1 Tg mice as compared with those of wild-type mice. Furthermore, NMDA-induced increase of p-CaMKIIα in retina of APP/PS-1 Tg mice was lower than that of wild-type mice. In ERG recordings, latencies of a-wave and oscillation potentials prolonged in APP/PS-1 mice as compared with those of wild-type mice.

Conclusions:: These findings suggest that Aß may attenuate activation of NMDA-receptor signaling pathways and retinal function.

Keywords: retina • phosphorylation • immunohistochemistry