Identification of a Novel Mechanism Fostering the Alterations of Brain Energy Metabolism: a Link Between AD and T2DM

Brain insulin resistance (bIR) is associated with mitochondrial stress, failure of energy metabolism, synaptic loss and ultimately neurodegeneration both in Alzheimer’s disease (AD) and Type 2-Diabetes Mellitus (T2DM). Our group previously demonstrated that loss of BVR-A is an early event triggering bIR in AD. Hence, we tested the hypothesis that reduced BVR-A levels link bIR and mitochondrial defects resulting in AD-like neuropathology in T2DM. Alterations of insulin signalling, autophagic flux, oxidative stress levels and AD hallmarks were analyzed in the hippocampus of wild-type and the goto-kakizaki (GK) model of T2DM rats. Hippocampal mitochondrial function was evaluated by measuring oxygen consumption rate (OCR), mitochondrial complexes, mitochondrial unfolded protein response (UPRmt) and oxidative stress levels. These data were correlated with peripheral metabolic measurements (fasting glucose, insulin and OGTT) and cognitive tasks (spatial memory). To confirm the role of BVR-A, similar analyses were performed in the hippocampus of WT and BVR-A KO mice fed a high fat diet (HFD, 60% kcal from fat) for 1, 3 or 8 weeks. Additional mechanistic insights were gained by evaluating mitochondrial function (sea-horse) and the above-mentioned intracellular pathways in response to insulin, in neuronal cells lacking BVR-A. GK rats displayed a diabetic phenotype and impaired spatial memory. Reduced BVR-A levels along with IRS1 hyper-activation and loss of Akt-mediated inhibition of GSK3ß were observed in the hippocampus, consistent with the regulatory role for BVR-A. As result, hyperactive GSK3ß accumulated in hippocampal mitochondria fostering their impairment characterized by reduced OCR and activation of UPRmt. Similar alterations in BVR-A KO mice and in neuronal cells lacking BVR-A were observed, reinforcing the role for BVR-A in regulating mitochondrial bioenergetics in response to insulin. HFD regimen promoted worse outcomes in BVR-A KO mice with respect to WT. Remarkably, gender-differences were observed whereby female mice show earlier and greater alterations with respect to male mice. These results suggest that early BVR-A loss triggers bIR and the hyper-action of GSK3ß, that, in turn, drives the development of mitochondrial stress in T2DM brain. These alterations accelerate the impairment of energy metabolism and development of AD-like neuropathology in T2DM.