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Peter Frederikse, Raj Kaswala, William Klein, Chinniswamy Kasinathan; Alzheimer Retina Pathology in a Novel Animal Model of Neuropathology in Diabetes. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5584.
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© ARVO (1962-2015); The Authors (2016-present)
Alzheimer pathology in retinal degeneration and diabetic retinopathy is key to understanding neuropathological mechanisms in this neural tissue in aging and diabetes. Considerable epidemiological, cell biology & clinical evidence links Alzheimer’s disease (AD) Abeta pathology with diabetes & insulin dysfunction. However, suitable animal models were cited as a block to understanding these relationships. We report on Alzheimer pathology in retina in diabetic genetically unmodified rabbits. The rabbit model includes system-wide physiological AbetaPP expression that normally generates human-sequence Abeta, which is key in AD studies, with relatively rapid onset of substantial pathology.
wt 4 mos-old NZ white rabbits were induced to become diabetic with alloxan and examined after 15 wks sustained blood glucose >350mg/dl. anti-Abeta peptide and oligomer-specific antibodies detected pathology in situ. Anti-RAGE detected Receptors for Advanced Glycation End-products, that increase with high glucose stimulated glycation reactions that also generate reactive oxygen species.
Substantial Abeta and RAGE accumulation occurred in ganglion cell and inner nuclear cell layers of diabetic retinas, with spontaneous production and accumulation of Abeta oligomers overlapping with Abeta in diabetic retinas. Abeta distribution in diabetic retinas was remarkably similar to accumulations in retina at 14 mos in classic Tg2576 AD mice, shown by others.
Substantial Abeta pathology was produced in the retina in a novel model of diabetic retinopathy in genetically unmodified rabbits, due to diabetes alone. Abeta oligomers, shown to be a key neurotoxic form of Abeta, were spontaneously produced in diabetic retinas and accumulated in ganglion cell and inner nuclear cell layers. Our study identifies emergence of Alzheimer pathology in the retina as a major consequence of diabetes; implicating dysfunctional insulin signaling in the relationship between Abeta neurotoxins and retinal degeneration in aging and diabetes, similar to brain. AD-type pathology in genetically unmodified rabbits calls attention to the considerable potential of the model for investigations of Alzheimer pathogenesis, diagnostics and therapeutics in the retina.
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