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Kumar Sambamurti, Emily Carley (Hollings), Zsolt Ablonczy, Craig E Crosson, Robert J Baranello, Vasudevaraju Padmaraju; Methionine restriction protects against γ-secretase impairment. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1315.
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© ARVO (1962-2015); The Authors (2016-present)
The Alzheimer’s amyloid β protein (Aβ) has been associated with a number of retinal degeneration conditions such as glaucoma and age related macular degeneration. Previous studies have shown that inhibition of γ-secretase impairs the barrier function of the retinal pigment epithelium (RPE) and retinal vascular endothelium. Protection against γ-secretase failure is therefore an important preventive measure for age related neurodegenerative diseases. We have examined the role of dietary amino acid restriction on γ-secretase and retinal sensitivity.
Cultured cells transfected with human Aβ precursor (APP), were restricted for methionine and media and cell lysates were evaluated for its metabolites. We also followed ARVO guidelines and developed a paradigm for feeding transgenic mice expressing human APP a synthetic control and methionine restricted diet (75%) for six months followed by scotopic electroretinography.
Methionine restriction did not result in a large reduction of membrane bound full-length APP. By contrast the carboxyl-terminal fragment generated by α-secretase cleavage of the precursor (CTFα) drastically dropped in levels. Addition of a γ-secretase inhibitor, significantly increased CTFα levels as expected. Interestingly, the relative levels of CTFα in control vs restricted cells was not as drastically different as in untreated cells suggesting that CTFα levels were regulated by reduced processing of the precursor to CTFα and also its increased turnover by γ-secretase. We therefore predict that such a restriction will be protective against γ-secretase impairment. Methionine restricted mice were then analyzed by ERGs. Methionine restricted mice showed similar weight gain and generally showed fewer losses than the control animals. In addition the A waves were slightly, but significantly larger and B waves were significantly faster in the restricted group of mice.
These studies provided evidence that methionine restriction protects APP-transgenic mice against loss of retinal sensitivity. The mechanisms in vivo await the euthanasia and analysis of the mice after 12 months, but one potential mechanism is by preservation of γ-secretase activity, which is crucial for the maintenance of membrane homeostasis.
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