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Marianne Phillips, Timothy Wong, Shereen Nizari, Yik L Chan, Hannah Whittington, Damian Cummings, M Francesca Cordeiro; A Study of Retinal Mitochondrial Changes in Aged Diabetic (Goto-Kakizaki) Rats to Explore Possible Links with Alzheimer’s Disease. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1710.
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Evidence suggests an association between Alzheimer’s Disease (AD) and Type 2 Diabetes Mellitus (T2DM). Metabolic disturbances, including hyperglycaemia, decreased insulin receptor sensitivity and mitochondrial dysfunction are common to both and can cause neuronal damage and degeneration. Studies also indicate that the retina may provide a non-invasive window to view the neuropathology in these conditions - notably via retinal ganglion cell layer (RGCL) thickness changes. Aberrant mitochondrial activity and AD-like pathology had previously been reported in the spontaneous T2DM Goto-Kakizaki rat model (D), but retinal neurones had not yet been studied so were of interest here.
Retinal sections were cut from 3, 12 and 18 month (m) D eyes and age-matched controls (C). Markers of mitochondrial permeability transition pore (mPTP) formation (VDAC and CypD), pro-apoptotic activity and apoptosis (cytochrome c and caspase-3) and electron transport chain activity (COX-1) were stained for, by immunohistochemistry. Confocal microscopy images were obtained, followed by grading to assess retinal changes in the 6 groups.
When compared to age-matched C, D showed significantly greater levels of staining for VDAC and caspase-3 - particularly at 12m (p<0.01 and p<0.001 respectively, with a minimum of n=3 per group). Unexpectedly, COX-1 showed significantly increased staining in D (p<0.001). CypD and cytochrome c showed a trend towards an increase in staining in D. Interestingly, the greatest staining occurred at 12m for all proteins, rather than the expected 18m.
As far as we are aware, this is the first study of retinal AD changes in the GK model and results indicate aberrant retinal mitochondrial activity, with increased mPTP formation and cell death. These findings resemble previous mitochondrial studies in the brain of other AD models, such as transgenic animals. They reinforce the increasing realization that both the retina and T2DM animals may model the neuropathology of AD. Thus, these results support T2DM as a current and future model of AD, especially as the pathology generated is sporadic - reflecting the majority of AD cases found clinically.
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