Alzheimer A–Beta Peptide Induces Macular Retinal Ganglion Cell Apoptosis

Abstract

Purpose: : The Alzheimer A–beta peptide (Abeta) is increasingly implicated in the cellular changes occurring in retinal disease. Although human histological studies have demonstrated Abeta involvement in ageing and age–related macular degeneration, this association has not been studied before in vivo. Furthermore, compared to other species, only human and non–human primates have a fovea and therefore non–human primates offer the most sophisticated model of macular disease. In this study, we investigate the effects of intravitreal Abeta on the primate retina.

Methods: : Five macaque monkey eyes received Abeta _25–35 (0.75–2.5 mg; Sigma UK, A4559) intravitreal injections whilst under general anaesthesia. Animals were imaged repeatedly at baseline and regular intervals post–operatively with an adapted confocal scanning laser ophthalmoscope (cSLO), following administration of fluorescent–labelled annexin 5 to evaluate apoptosis, as previously described. After the final imaging, animals were killed and the eyes examined histologically.

Results: : Abeta_25–35 induced significant retinal ganglion cell (RGC) apoptosis, but more strikingly, with a predilection for the parafoveal area, as confirmed with careful anatomical reconstructions both with a confocal microscope and with serial transverse histological sections. There was a concentration– and time–dependent effect, with maximal apoptosis at 2.5 mg and after 16 hours after Abeta administration. The density of apoptosing RGCs around the macula, at maximal levels histologically, was measured as 30,541/mm² compared to the normal RGC density of 48,982/mm².

Conclusions: : This study demonstrates for the first time in vivo that Abeta _25–35 induces a macular specific pattern of apoptosis, which may have implications for retinal disease. Whether this is due to a greater sensitivity of macular cells to Abeta effects or the increased density of RGCs in this area is yet to be established.

Keywords: apoptosis/cell death • age-related macular degeneration • imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound)