engleski

AD - AN insulin resistant brain state

Reports of impaired brain insulin receptor (IR) signaling being involved in cognitive decline, affecting also glucose utilization and energy metabolism, cell growth and differentiation, as well as metabolism of amyloid beta (Aβ ) and tau protein, have drawn an increasing attention in Alzheimer’ s disease (AD) research. A growing body of evidence indicates indeed that sporadic type of AD (sAD) is associated with brain IR signaling abnormalities. Due to the slow, symptoms-free onset of sAD, their real role in sAD pathophysiology has remained unclear, leaving the follow up of IR dysfunction development to the animal AD models. Rats that have been intracerebroventricularly treated with streptozotocin (STZ-icv), a drug selectively toxic for insulin producing/secreting cells and IR, have been recognized recently as the experimental sAD model. Previous research of STZ-icv rat model reviled AD-like alterations ; progressive memory deficits, decreased cholinergic transmission, reduced glucose/energy metabolism, oxidative stress, gliosis and neuronal loss in the brain. We investigated the time course and nature of brain insulin system dysfunction in this sAD model. Our results demonstrated alterations starting from the decreased insulin gene expression, followed by a decreased expression of IR mRNA and protein, found as early as 1 month following the induction of sAD-like condition and persisting up to 6 months afterwards. Downstream the IR-phosphatydilinositol-3 kinase signaling pathway decreased protein kinase Akt/PKB expression followed by a decreased phosphorylated/non-phosphorylated glycogen synthase kinase-3 (GSK-3α /β ) ratio, suggesting increased GSK-3 activity, was found not earlier than 3 months after the induction of sAD-like condition. This has eventually led to tau protein hyperphosphorylation and Aβ aggregation found not earlier than 3 months after the disease induction as the cerebral amyloid angiopathy followed by a primitive plaque-like formation 6 months after the STZ-icv treatment. Therefore, sAD could be considered as an insulin resistant brain state which precedes and eventually triggers Aβ pathology.

Alzheimer disease; insulin resistant brain state; streptozotocin

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