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Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer’s disease

  • Neurology and Preclinical Neurological Studies - Original Article
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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.

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Acknowledgments

The research has been done in collaboration with Professor Siegfried Hoyer whom we dedicate this paper and whose ideas shall carry us a long way in the future sAD research. Supported by The Croatian Ministry of Science, Education and Sports (project No 108-10800003-0020) and German Academic Exchange Service (DAAD).

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Authors and Affiliations

  1. Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 11, HR 10000, Zagreb, Croatia

    J. Osmanovic Barilar, A. Knezovic & M. Salkovic-Petrisic

  2. Neurobiochemistry Laboratory, University Clinics of Child and Adolescent Psychiatry, University of Zürich, Wagistrasse 12, 8952, Schlieren, Switzerland

    E. Grünblatt

  3. University Hospitaly, Clinic and Policlinic of Psychiatry, Psychosomatic and Psychotherapy, University of Wuerzburg, Fuechsleinstr. 15, 97080, Würzburg, Germany

    P. Riederer

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  1. J. Osmanovic Barilar
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Osmanovic Barilar, J., Knezovic, A., Grünblatt, E. et al. Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer’s disease. J Neural Transm 122, 565–576 (2015). https://doi.org/10.1007/s00702-014-1323-y

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  • DOI: https://doi.org/10.1007/s00702-014-1323-y

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