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A. Prakasam, M. A. Pappolla, B. Rohrer, K. Sambamurti; Changes in the Alzheimer’S Amyloid Protein Precursor Metabolism During Light-Induced Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4410.
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The amyloid β protein deposited in Alzheimer’s disease (AD) as well as in the drusen of Age Related Macular Degeneration (AMD) is processed by multiple complex pathways in the brain. The purpose of this study is to determine whether Amyloid protein precursor (APP) processing in the eye is altered during light-induced retinal degeneration.
Dark adapted BALBC mice were exposed to continuous low or high intensity light for a range of time form 0 to 12 days and eyes were collected dissected to obtain the vitreous humor, the retina and retinal pigmented epithelial cell (RPE) layers. Eyes of mice were carefully dissected to obtain the RPE, retina and vitreous humor fractions from control and γ-secretase inhibitor treated animals. These fractions were analyzed by Western blotting with either peptide or protein gels as appropriate to detect secreted or membrane-bound precursor proteins and cleavage products using commercial and in house antibodies against various domains of APP, Nicastrin, Presenilin.
Light induces the loss of photoreceptor with time and the accumulation of C-terminal fragments of APP derived from α- and β-secretase pathways. A similar pattern of CTFα/CTFβ accumulation is also seen in rd1 (retinal degeneration) and rd2 mice undergone photoreceptor degeneration. Intense light promotes accumulation of CTFs during the Day 2 onwards where as low light intensity promotes day 6 onwards. This accumulation can be explained by the failure of γ-secretase, which normally generates Aβ and efficiently eliminates the CTFs. Consistent with this interpretation, several γ-secretase subunits are altered in the light-damaged retina.
These studies suggest that failure of γ-secretase is associated with early stages of retinal degeneration induced by light and mutations. These studies suggest that rather than inhibition, methods to preserve this activity must be adopted to protect against AMD.
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