engleski

Brain insulin system and sporadic Alzheimer's disease: experimental approach

Decreased brain glucose/energy metabolism and cognitive deficits similar to those found in sporadic Alzheimer’ s disease (sAD), were reported in streptozotocin (STZ)-intracerebroventricularly (icv) treated rats, suggesting them as a probable experimental model of this disease. Initial pathophysiological changes and their course in the human brain are not completely understood. Alterations of brain insulin receptor (IR) signaling have been found in human sAD. Since STZ is selectively toxic to insulin producing/secreting cells, elements of brain IR signaling cascade, protein kinase B/Akt (PKB/Akt) and glycogen synthase kinase-3 (GSK-3) and time-course of their changes in STZ-icv treated rats were investigated. Cognitive deficits (Morris Water Maze Swimming Test), brain neurochemical changes of IR signalling elements (Western blot), and structural beta amyloid-related changes (Congo red staining) were measured 1 and 3 months following the STZ-icv (1 mg/kg) treatment. Mild decrease in hippocampal PKB/Akt was 3 months after the STZ-icv treatment in hippocampus, but not in frontal cortex. Relative pGSK-3/GSK-3 protein ratio was found increased (+50%) after 1, but decreased (-9%) after 3 months in hippocampus, and decrease after 1 and 3 months in frontal cortex of STZ-icv rats suggesting increment in non-phosphorylated, active form of GSK-3. In line with possible GSK-3 β subunit hyperactivity, total tau protein expression was found significantly increased after 1 month, while both total and phospho tau protein expression were intensively increased after 3 months. In addition, diffuse congophilic, beta amyloid-like aggregates were found in the meningeal capillaries three months after STZ-icv treatment. Cognitive deficits in learning and memory in STZ-icv rats were more pronounced in a longer post-treatment period. Based on the experimental model of sAD, brain IR signaling alterations may be an important factor in sAD generation, preceding β -amyloid and tau protein related pathological hallmarks of sAD. Supported by the Croatian Ministry of Science, Sports and Education, and DAAD.

insulin; brain; Alzheimer's disease; streptozotocin

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