GAL-101 prevents amyloid beta-induced membrane depolarization in two different types of retinal cells

Abstract

Glaucoma and age-related macular degeneration (AMD) are two of the major causes of progressive vision loss and ultimately blindness worldwide. Both retinopathies share several pathological features with Alzheimers disease (AD) such as: impairment of neuronal function, astrocytosis, and activation of immune-competent microglia and Muller cells. It also has been shown that these conditions are characterized by the presence of an elevated concentration of amyloid beta (A{beta}). Under pathological conditions, A{beta}1-42 tends to aggregate, forming toxic soluble oligomers, considered to be the most harmful amyloid species. One strategy adopted to prevent cell damage caused by these oligomers is to impair their aggregation. Here we studied GAL-101, a small molecule designed to modify the aggregation of A{beta}1-42. To assess the role of GAL-101 in the aggregation of A{beta}1-42, in vitro electrophysiological measurements on retinal ganglion cells (RGCs) and retinal pigment epithelial (RPE) cells were performed to determine the polarization of the resting membrane potential. Cells treated only with A{beta}1-42 oligomers showed a strong depolarization of the resting membrane potential, which is believed to be the main reason for retinal cells malfunctioning in neurodegenerative diseases of the eye. Pre-incubation with GAL-101 stabilized the cell resting potential to around -50mV during exposure to A{beta}1-42, in both RGCs and RPE cells. GAL-101 was able to prevent changes in resting membrane potential and thus would be expected to prevent impairment of retinal cell function. These results are supportive of evaluating GAL-101 as a potential treatment of A{beta}-associated retinopathies like glaucoma and dry AMD.