engleski

Glucose Transporter Type 2 - Does It Pave the Way to Sporadic Alzheimer's Disease?

Background: Sporadic type of Alzheimer&#8217; s disease (sAD) is associated with brain insulin receptor (IR) signalling abnormalities. The sequence of these events in relation to the beta amyloid (A&#946; ) pathology can be traced only in sAD animal model, rats treated intracerebroventricularly with streptozotocin (STZ-icv). STZ enters the cell through glucose transporter type 2 (GLUT2) and selectively damages insulin producing/secreting cells and IR, as well as GLUT2. The time course of brain insulin system dysfunction following damage induced by icv application of GLUT2- and IR-toxic drug was investigated in this sAD model. Methods: Male Wistar rats (3-4 month old, 6-8 per group) were treated bilaterally icv with STZ (1-3 mg/kg) and followed after 1, 3 and 6 months for the memory (Morris Water Maze Swimming Test), hippocampal neurochemistry (RT-PCR for insulin-1 /Ins-1/, IR and insulin degrading enzyme /IDE/, immunoblotting for IR, protein kinase B /Akt/PKB/, glycogen synthase kinase 3 /GSK-3/, IDE, tau protein, and Elisa assay for tyrosine kinase /TK/), and histology (immunohistochemistry and Congo red staining for A&#946; ). Data were analysed by Kruskal Wallis median and Mann Whitney U test. Results: One month following the STZ-icv treatment IR mRNA and protein were decreased (p<0.05). Three months following the STZ-icv treatment Ins-1 and IR mRNA were decreased (p<0.05) and IR-TK activity increased (p<0.05). This was followed by alterations (p<0.05) of downstream IR signaling elements, decreased expression of Akt/PKB and p-GSK-3/GSK-3 ratio, increased expression of hyperphosphorylated tau protein, and decreased expression of IDE mRNA and protein. A&#946; -like congophilic capillary aggregates (cerebral amyloid angiopathy) and A&#946; 1-42 intraneuronal aggregates were found after 3 months. Decreased expression of Ins-1, IR and IDE mRNA, IR and IDE protein were found 6 months after STZicv treatment when A&#946; 1-42 primitive plaques were found in hippocampal/cortical regions. Cognitive deficits were found at each time point. Conclusions: STZ-icv induced damage of brain GLUT2 and IR leads to insulin resistant brain state eventually triggering A&#946; pathology in animal sAD model. Supported by DAAD and MZOS.

sporadic Alzheimer disease; insulin receptor; brain; GLUT-2; amyloid beta

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