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Kumar Sambamurti, Beth Coughlin, Craig E. Crosson, Zsolt Ablonczy, Baerbel Rohrer, Annamalai Prakasam; Alzheimer’s Disease Pathways and Retinal Function. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1376.
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Several studies have linked retinal degeneration with Alzheimer’s disease. In particular, its is reported that amyloid deposits in the eyes of Age related Macular degeneration and Glaucoma subjects. Based on the most popular amyloid hypothesis that forms the basis of most drug development efforts against Alzheimer’s disease, theories suggest that amyloid accumulation may cause neurodegeneration in retinal degenerative disorders. Our goal is to better understand the role of the Alzheimer’s amyloid protein precursor and its processing pathways on retinal function.
We have generated human Alzheimer’s amyloid protein precursor (APP) expressing transgenic mouse models in the BALB-c background and have determined their effects on scotopic ERGs. Further, we have treated BALB-c mice with a known γ-secretase inhibitor and examined its effect on ERG patterns. Mice used in this study were 3-4 months of age to avid studying the effects of amyloid deposition.
APP transgenic mice showed significant increases in both a- and b-wave amplitudes in comparison to their non-transgenic controls. In addition, a two-day treatment with a γ-secretase inhibitor, LY411575, resulted in a significant inhibition of b-waves without an accompanying significant effect on a-waves. The mice recover from this early inhibition by 10 days of treatment and ERG signals return to normal. Exposure to continuous white light for 10 days substantially reduced a- and b-waves in control and treated BALB-c mice as expected, but the effect was substantially exacerbated in the LY411575-treated mice.
APP transgenic mice exhibit increased photoreceptor and bipolar cell responses. Although the data are consistent with several reports showing that Aβ facilitates synaptic activity, it is unlikely that these mice show substantial Aβ accumulation at this young age. The inhibition of γ-secretase impairs synaptic transmission from the photoreceptors to the bipolar cells, an effect that is exacerbated upon light-induced photoreceptor cell damage. Take together, we conclude that γ-secretase plays an important role in neuronal function and neuroprotection and therefore its impairment may lead to age-related neurodegenerative diseases.
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