engleski

Brain insulin receptor signaling cascade in experimental rat model related to the human sporadic Alzheimer's disease

Aim. Due to the slow, often imperceptible onset, and nature of the sporadic Alzheimer’ s disease (sAD), initial pathophysiological changes and their further course in the human brain are unknown, making the search for an appropriate experimental model even more difficult. Decreased brain glucose/energy metabolism and cognitive deficits similar to those found in sAD, were reported in streptozotocin (STZ)-intracerebroventricularly (icv) treated rats, suggesting them as a probable experimental model of this disease. Study was aimed to explore the elements of brain insulin receptor (IR) signaling cascade and time-course of their changes in STZ-icv treated rats. Methods. Cognitive deficits (Morris Water Maze Swimming Test), neurochemical changes of IR signalling cascade elements (Western blot), gene expression changes of insulin-like growth factor 1 (IGF-1) receptor (quantitative-RT-PCR) and structural changes in beta amyloid aggregates (Congo red staining) in the brain of STZ-icv (1 mg/kg) rats, were measured ≤ three months following the STZ-icv treatment. Results. Hippocampal protein kinase B/Akt levels were mildly but insignificantly increased after one month, and mildly but significantly decreased (-9%) three months after STZ treatment. In line with that, the relative phosphorylated/non-phosphorylated glycogen synthase kinase-3 α /β , pGSK-3α /β /GSK-3α /β ratio in hippocampus was found significantly increased (+50%) after one, and decreased (-9%) after three months. Mild increase in hippocampal total tau expression was found one month after STZ-icv treatment. Diffuse congophilic, beta amyloid-like aggregates were found in the meningeal capillaries three months after STZ-icv treatment. mRNA expression of IGF-1 receptor which shares signaling cascade pathway with IR and could compensate IR dysfunction, has been found decreased in the brain of STZ-icv treated rats. Neurochemical and structural changes in STZ-icv treated rats were accompanied by cognitive deficits that were more pronounced with a longer duration of post-treatment period (-46% after three months vs. -33% after one month) Conclusion. STZ-icv rat model shares similarities with human sAD at the behavioural, structural and neurochemical level, and suggests that brain IR signaling alterations, observed in humans post-mortem mostly in the late stage of disease, may in fact be an early trigger in sAD generation. Acknowledgement. Supported by the Croatian Ministry of Science, Sports and Education, and DAAD.

insulin receptor; brain; streptozotocin; Alzheimer's disease

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