engleski

. Insulin resistant brain state triggers amyloid beta pathology in experimental sporadic Alzheimer's disease.

Pathological assemblies of amyloid beta (A&#946; ) in the brain are thought of as the primary cause of all Alzheimer&#8217; s disease (AD) forms, whereas other neuropathological changes being just downstream consequences. Among them, impairments in brain insulin receptor (IR) signaling have been implicated in the pathophysiology of the prevailing, sporadic late-onset AD (sAD) type. Our current work reviews evidence of brain insulin system dysfunction as a primary pathological event influencing tau protein and A&#946; expression in streptozotocin-intracerebroventricularly (STZ-icv) treated rats proposed as an experimental model of sAD which is not related to gene manipulation. Gene and protein expression of insulin and IR (quantitative RT-PCR, ELISA), tyrosine kinase (TK) activity, protein kinase B/Akt (PKB/Akt) and phospho-to total-glycogen synthase kinase 3&#945; &#946; (pGSK3&#945; &#946; /GSK3&#945; &#946; ) ratio, as well as tau protein (Western blot) and A&#946; 1-42 expression (immunohystochemistry, Western blot, A&#946; Congo red staining) were measured and visualized in rat frontoparietal cortex (CTX) and hippocampus (HPC) one, three and six months following the STZ-icv (1-3 mg/kg) treatment. Time course of cognitive deficits was measured by Morris Water Maze Test. Data were analyzed by Cruscal-Walles ANOVA and Mann-Whitney U test (P<0.05). One month following the STZ-icv treatment insulin and IR mRNA was found significantly decreased in both regions, phosphorylated IR-&#61538; subunit expression has been unchanged (HPC) or increase (CTX), while significantly increased TK activity was found in HPC only. PKB/Akt expression and pGSK3&#945; &#946; /GSK3&#945; &#946; ratio were found decreased (HPC) but not earlier than 3 month following the drug treatment. One month after the drug treatment only mild increase in total tau expression was observed while after three months GSK-3 related tau protein hyperphosphorylation was found in HPC. A&#946; -like congophilic aggregates in meningeal capillaries and A&#946; 1-42 intracellular aggregates were found not earlier than 3 months after STZ-icv treatment and were followed by A&#946; 1-42-formed primitive plaques in HPC and cortical region six months after STZ-icv treatment. Cognitive deficits were found as early as 2 weeks after STZ-icv treatment. STZ-icv treatment induced modeling of sAD provided convincing evidence that instead of A&#946; pathology, imbalance in IR signaling cascade phosphorylation/dephosphorylation and insulin resistant brain state could be a pathological core in generation of sAD, an early event which in the course of disease leads to development of AD neuropathological hallmarks, A&#946; plaques and tau protein hyperphosphorylation. Supported by Croatian MZOS (108-1080003-0020) and DAAD.

Brain Insulin; Streptozotocin; Alzheimer's Disease

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