engleski

Modelling sporadic Alzheimer’ s disease.

Based on similarities in cognitive deficits and decreased brain glucose/energy metabolism and oxidative stress, streptozotocin-intracerebroventricularly (STZ-icv) treated rats were proposed as the experimental sporadic Alzheimer&#8217; s disease (sAD) model which is not related to gene manipulations. To further characterize this model we investigated the brain insulin system and influence of its dysfunction on tau protein and amyloid beta (A&#946; ) peptide. Gene expression of insulin and insulin receptor (IR), alterations of IR-beta subunit, IR tyrosine kinase (TK) activity, expression of protein kinase B (Akt/PKB), glycogen synthase kinase 3 (GSK-3) and tau protein were measured by RT-PCR, ELISA, TK assay and Western blot in frontoparietal cortex (CTX) and hippocampus (HPC) of adult STZ-icv (1 mg/kg) treated rats. A&#946; aggregates were visualised by Congo red staining. Cognitive deficits were measured in Morris Water Maze Test. Data were analysed by Cruscal-Walles ANOVA and Mann-Whitney U test (P<0.05). Expression of insulin-1 (HPC) and -2 (CTX) and IR mRNA (CTX, HPC) was decreased. Phosphorylated IR-beta subunit content was increased (CTX) and TK activity increased (HPC). Akt/PKB and phosphorylated/non-phosphorylated GSK-3&#945; /&#946; ratio were decreased (HPC) GSK-3-related hyperphosphorylation of tau protein (HPC) and A&#946; aggregates in meningeal capillaries were found not earlier than 3 months after STZ-icv treatment. Cognitive deficits were found as early as 2 weeks after STZ-icv treatment. STZ-icv is a representative experimental sAD model which, in general, shares with human sAD also region- and time-dependent similarities in brain insulin system dysfunction. Such a modelling of sAD enabled the conclusion that instead of A&#946; , imbalance in IR signaling cascade phosphorylation/dephosphorylation and insulin resistant brain state could be the primary pathological event in sAD ethiopathogenesis. Supported by Croatian MZOS (108-1080003-0020) and DAAD.

Animal models; Sporadic Alzheimer's Disease; Streptozotocin

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