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Timothy Wong, Marianne Phillips, Doris Chan, Shereen Nizari, Damian Cummings, M Francesca Cordeiro; A study of aged GK rats: is tau the missing link between diabetes and Alzheimer’s Disease?. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1721.
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Recent research has shown that despite their different features, diabetes and Alzheimer’s disease (AD) share similar pathophysiology including abnormal glucose metabolism, insulin resistance and impaired insulin signalling. AD is the most common type of dementia and its pathological hallmarks include extracellular β-amyloid plaques and intracellular neurofibrillary tangles (NFTs). Diabetes is a metabolic condition characterized by insulin deficiency (Type 1), insulin resistance and defective insulin signalling (Type 2). Patients with Type 2 diabetes (T2DM) have an approximately 60% increased risk of developing AD. Goto Kakizaki (GK) rats are spontaneously diabetic and are considered a model for T2DM in humans. As the brain and retina share a common embryological origin, we have hypothesised that AD pathology in the brains of AD transgenic mice also occurs in the retina. Here, we investigate whether tau pathology and neurofilamentopathy are present in the retinas of aged GK rats.
The eyes from 3-, 12- and 18-month old spontaneously diabetic GK rats (n=4 for each age group) and age-matched controls (n=3 for 3-month old; n=4 for 12- and 18-month old) were obtained and embedded in paraffin blocks. Sections from these blocks were stained with antibodies for tau, hyperphosphorylated tau (p-tau) and NF-heavy (NFH). Immunohistochemistry images were visualized and obtained. These images were graded for distribution and fluorescence of the antibodies by three independent observers without knowledge of diabetic or control status.
Analysis showed an age-dependent increase of p-tau (p<0.001) and NFH (p<0.001) in the diabetic retina, but not the control retina. Increased levels of p-tau (p<0.01) and NFH (p<0.001) were found in the diabetic retina as compared to the age-matched control retina. No change of colocalization of p-tau and NFH was found in the control or diabetic retina over time.
Recent evidence has suggested that neurodegeneration is an early phenomenon in DM. This study demonstrated an increase in tau-associated neurodegeneration in the diabetic retina over time and as compared to the control retina. As far as we are aware, this is the first study demonstrating AD tau pathology in the retinas of aged diabetic GK rats.
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