Amyloid-β and Tau Pathology of Alzheimer's Disease Induced by Diabetes in a RABBIT Animal Model

Alzheimer's disease (AD) is the major age-dependent disease of the brain, but what instigates late-onset AD is not yet clear. Epidemiological, animal model, and cell biology findings suggest links between AD and diabetes. Although AD pathology is accelerated by diabetes in mice engineered to accumulate human-sequence amyloid-beta (A beta) peptides, they do not adequately model non-inherited AD. We investigated AD-type pathology induced solely by diabetes in genetically unmodified rabbits which generate human-sequence A beta peptides. After 15 weeks, alloxan-treated diabetic rabbits with expected high blood glucose showed similar to 5-fold increase in A beta(40)/A beta(42) in cortex and hippocampus, and significantly, generated A beta-derived assemblies found in human AD. Deposits of these putative pathogenic toxins were detected by A beta/A beta oligomer antibodies in brain parenchyma and surrounding vasculature, also co-localizing with markedly elevated levels of RAGE. Soluble brain extracts showed diabetes-induced buildup of A beta oligomers on dot-blots. Phospho-tau also was clearly elevated, overlapping with beta III-tubulin along neuronal tracts. Indications of retina involvement in AD led to examination of AD-type pathology in diabetic retinas and showed A beta accumulation in ganglion and inner nuclear cell layers using A beta/oligomer antibodies, and RAGE again was elevated. Our study identifies emergence of AD pathology in brain and retina as a major consequence of diabetes; implicating dysfunctional insulin signaling in late-onset AD, and a potential relationship between A beta-derived neurotoxins and retinal degeneration in aging and diabetes, as well as AD. AD-type pathology demonstrated in genetically unmodified rabbits calls attention to the considerable potential of the model for investigation of AD pathogenesis, diagnostics, and therapeutics.