engleski

Brain insulin system dysfunction as a trigger for plaque formation in rat model of sporadic alzheimer's disease (a survey)

Amyloid cascade hypothesis takes for granted that pathological assembly of amyloid beta (Aβ) in the brain is the primary cause of all Alzheimer’s disease (AD) forms, whereas other neuropathological changes, including the brain insulin system dysfunction found post-mortally in AD patients, are just downstream consequences. The time-course of AD pathology development is investigated in experimental models, the representativeness of which is often a matter of dispute. While transgenic mice have been the most frequently used as animal AD models in general, due to manipulation of genes involved in Aβ- generation, these models could represent rare cases of familiar AD form only. Streptozotocin- intracerebroventricularly (STZ-icv) treated rats have been recently proposed as a model for the sporadic AD form. STZ is a cytotoxic drug which, after peripheral administration, has been found selectively toxic for the insulin producing/secreting cells and insulin receptor (IR). Previous research of STZ-icv rat model by other groups has been done up to 3 months following the STZ-icv application, demonstrating progressive cognitive deficits in learning and memory functions, decreased cholinergic transmission in the brain, as well as decreased brain glucose/energy metabolism, oxidative stress, glyosis and apoptosis. We have done extensive time-course study of rat brain insulin and insulin receptor (IR) signalling in a period of 1 - 6 months following the STZ-icv application. Our results suggest time-dependent development and escalation of dysfunction in brain insulin and IR signalling cascade downstream the phosphatydil-inositol 3 kinase (PI-3K) pathway in hippocampus (HPC). One month after STZ-icv administration only decreased expression of brain IR gene and protein was found with no changes in Akt/PKB protein expression and phospho- to total- glycogen synthase kinase 3 (GSK-3) ratio, as well as no change in GSK-3 related phospho-tau protein expression. Also, histology techniques showed no Aβ accumulation at this time point. Three months after STZ-icv administration persisting decrease in expression of IR gene and protein was followed actually by a development of insulin resistant brain state ; decreased expression of insulin I gene, and a progression of signalling impairment downstream the PI-3K pathway, demonstrated as decreased expression of Akt/PKB protein, decreased phospho/total GSK-3 ratio and tau protein hyperphosphorylation. Furthermore, signs of Aβ pathology appeared as a cerebral amyloid angiopathy and intraneuronal Aβ1-43 accumulation in cortico-hippocampal region. Six months after STZ-icv administration, the changes of insulin, IR, GSK-3 and tau protein were still persisting. However, previously found Aβ pathology further escalated with appearance of few amyloid primitive plaques in the cortical region. Animals showed deficits in learning and memory during the whole 6 month period. Our results strongly suggest that insulin resistant brain state, developed in this model by STZ-icv treatment, precedes and induces time- dependent Aβ pathology and plaque development in experimental sAD. Considering the similarities between the human sAD and STZ-icv rat model, it seems likely that, contrary to the amyloid cascade hypothesis, insulin resistant brain state could be a pathological core in generation of sAD in humans.

Alzheimer's disease; streptozotocin; insulin receptor; amyloid beta; glycogen synthase kinase 3

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