Statement of the Problem: Epidemiological and neuroimaging evidence indicates a shared pathophysiology between Alzheimer’s disease (AD) and Type 2 Diabetes (T2DM). AD brains show glucose hypo-metabolism and insulin resistance that correlates with increased number of neuritic plaques leading to the hypothesis that AD might be Type 3 Diabetes. One of the pathological hallmarks of AD brain is neurofibrillary tangles composed of hyper-phosphorylated tau protein. Utilizing our Drosophila model of Tauopathy we have elucidated the mechanistic linkage between the exacerbation of tau pathology and insulin resistance thereby suggesting a link between AD and T2DM. The biochemical changes observed in vivo have been complemented in vitro using SHSY5Y cell lines.
Methods and Materials: The longest isoform of human tau (2N4R) was driven in the Drosophila eye using an eye-specific GMR-Gal4 driver to generate GMR-Gal4-glTau transgenics or pan-neuronally by Elav-Gal4. These transgenics were combined to mutant flies from the insulin signalling pathway obtained from Bloomington stock centre Indiana. The biochemical, immunohistochemistry and behavioural assays were performed by standard published methods.
Results: Utilizing genetic interactions and biochemical analysis, we observed that in an “insulin-resistant” condition, the Drosophila tauopathy models demonstrated a worsening of tau-induced neurotoxicity, hyperphosphorylation and formation of aggregates. In addition, under insulin-resistant state we observed significant alterations in the TOR and autophagy pathway components suggesting that the tau toxicity under these conditions was mediated partly by impaired tau clearance. Interestingly, these pathological features were ameliorated in an “insulin sensitive” state. These results were further replicated in SHSY5Y cell lines.
Conclusions: Insulin resistance plays an important role in mediating tau-induced pathology via interlinked pathways conserved in vitro and in vivo. Our findings elucidate shared pathophysiological connections between AD and T2DM that may be important for early AD diagnostics and future therapeutic studies.