P3‐146: Decline in mitochondrial bioenergetics underlies central insulin resistance in streptozocin‐induced model of sporadic Alzheimer's disease

Early abnormalities in cerebral glucose/energy metabolism are consistent antecedents to sporadic Alzheimer's disease (sAD) development, suggesting that impaired insulin signaling is present at the earliest symptomatic stages of the disease. Additionally, cerebral metabolism decline also points for a potential causal role of mitochondrial bioenergetics in sAD pathogenesis. In this study we investigated the impact of central insulin resistance on mitochondrial bioenergetics by using rats intracerebroventricularly (icv) treated with streptozotocin, an animal model of sAD. Three-month-old male Wistar rats were investigated 5 weeks after a single bilateral icv injection of STZ (3mg/Kg) or vehicle. Both cortical and hippocampal mitochondria from icvSTZ rats exhibit impaired oxidative phosphorylation system characterized by decreased mitochondrial transmembrane potential and ADP depolarization and increased lag phase of repolarization, when compared with mitochondria isolated from vehicle-treated rats. Consistently, icvSTZ rats also present decreased mitochondrial respiratory state 3, respiratory control ratio, ADP/O index and DNP-stimulated respiration, in the presence of complexes I (glutamate/malate) or II (succinate) substrates, whereas state 4 remained unaltered. A decrease in pyruvate dehydrogenase, a-ketoglutarate dehydrogenase and cytochrome c oxidade activities was also observed, which reinforces the existence of mitochondrial bioenergetic deficits in this animal model of sAD. icvSTZ rats also display an increased susceptibility to calcium-induced mitochondrial permeability transition, a phenomenon that could be related with the decrease in hexokinase activity. Altogether, these results strongly suggest that mitochondrial bioenergetics decline is intimately associated with the “insulin-resistant brain state” in this animal model of sAD, highlighting the central importance of mitochondrial (dys)function in the pathology of the disease.