title: Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer's disease.
abstract: Sporadic Alzheimer disease (sAD) is associated with impairment of insulin receptor (IR) signalling in the brain. Rats used to model sAD develop insulin-resistant brain state following intracerebroventricular treatment with a betacytotoxic drug streptozotocin (STZ-icv). Brain IR signalling has been explored usually at only one time point in periods ≤3 months after the STZ-icv administration. We have investigated insulin signalling in the rat hippocampus at five time points in periods ≤9 months after STZ-icv treatment. Male Wistar rats were given vehicle (control)- or STZ (3 mg/kg)-icv injection and killed 0.5, 1, 3, 6 and 9 months afterwards. Insulin-1 (Ins-1), IR, phospho- and total (p/t)-glycogen synthase kinase 3-β (GSK-3β), p/t-tau and insulin degrading enzyme (IDE) mRNA and/or protein were measured. Acute upregulation of tau and IR mRNA (p < 0.05) was followed by a pronounced downregulation of Ins-1, IR and IDE mRNA (p < 0.05) in the course of time. Acute decrement in p/t-tau and p/t-GSK-3β ratios (p < 0.05) was followed by increment in both ratios (3-6 months, p < 0.05) after which p/t-tau ratio demonstrated a steep rise and p/t-GSK-3β ratio a steep fall up to 9 months (p < 0.05). Acute decline in IDE and IR expression (p < 0.05) was followed by a slow progression of the former and a slow recovery of the latter in 3-9 months. Results indicate a biphasic pattern in time dependency of onset and progression of changes in brain insulin signalling of STZ-icv model (partly reversible acute toxicity and chronic AD-like changes) which should be considered when using this model as a tool in translational sAD research.
authors.affiliation: Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 11, HR 10000, Zagreb, Croatia, josmanov@mef.hr.
authors.forename: J Osmanovic
authors.initials: JO
authors.lastname: Barilar
authors.forename: A
authors.initials: A
authors.lastname: Knezovic
authors.forename: E
authors.initials: E
authors.lastname: Grünblatt
authors.forename: P
authors.initials: P
authors.lastname: Riederer
authors.forename: M
authors.initials: M
authors.lastname: Salkovic-Petrisic
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005500:Follow-Up Studies; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism*; D007339:Insulysin / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction; D013311:Streptozocin; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism
chemical_list: C489131:Mapt protein, rat; D012333:RNA, Messenger; D016875:tau Proteins; D013311:Streptozocin; D011972:Receptor, Insulin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D007339:Insulysin