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Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer’s disease

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

Sporadic Alzheimer’s disease (sAD) is the most common form of dementia. Rats injected intracerebroventricularly with streptozotocin (STZ-icv) develop insulin-resistant brain state and represent a non-transgenic sAD model with a number of AD-like cognitive and neurochemical features. We explored cognitive, structural and ultrastructural changes in the brain of the STZ-icv rat model over a course of 9 months. Cognitive functions were measured in the STZ-icv- (0.3, 1 and 3 mg/kg) and age-matched control rats by passive avoidance test. Structural changes were assessed by Nissl and Bielschowsky silver staining. Immunohistochemistry and electron microscopy analysis were used to detect amyloid β- (Aβ1-42) and hyperphosphorylated tau (AT8) accumulation and ultrastructural changes in the brain. Memory decline was time- (≤3 months/acute, ≥3 months/progressive) and STZ-icv dose-dependent. Morphological changes were manifested as thinning of parietal cortex (≥1 month) and corpus callosum (9 months), and were more pronounced in the 3 mg/kg STZ group. Early neurofibrillary changes (AT8) were detected from 1 month onward in the neocortex, and progressed after 3 months to the hippocampus. Intracellular Aβ1-42 accumulation was found in the neocortex at 3 months following STZ-icv treatment, while diffuse Aβ1-42-positive plaque-like formations were found after 6 months in the neocortex and hippocampus. Ultrastructural changes revealed enlargement of Golgi apparatus, pyknotic nuclei, and time-dependent increase in lysosome size, number, and density. Our data provide a staging of cognitive, structural/ultrastructural, and neuropathological markers in the STZ-icv rat model that in many aspects seems to be generally comparable to stages seen in human sAD.

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Acknowledgments

The paper is dedicated to Professor Sigfried Hoyer, the pioneer in the field of streptozotocin-induced rat model of sporadic Alzheimer’s disease who greatly contributed to initiation of this research. The research was supported by the Unity Through Knowledge Fund (original UKF project 10/64), the Deutscher Akademischer Austausch Dienst (DAAD 2006–2010), the Croatian Ministry of Science, Education and Sports (grant. no. 108-1081870-1942) and the Croatian Science Foundation (grant. no. 09/16). Dr. R. Kuljis is thanked as a co-PI in the initial part of the UKF project. Prof. S. Gajovic provided help and support with electron microscopy. Dr. C. Monoranu provided helpful immunohistochemistry expertise.

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The authors declare no conflict of interest.

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Authors and Affiliations

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

    Ana Knezovic, Jelena Osmanovic-Barilar & Melita Salkovic-Petrisic

  2. Department of Histology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 12, 10000, Zagreb, Croatia

    Marija Curlin

  3. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Patrick R. Hof

  4. Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 12, 10000, Zagreb, Croatia

    Goran Simic

  5. Center of Psychic Health, Clinic and Policlinic for Psychiatry and Psychotherapy, University Hospital Würzburg, 97080, Würzburg, Germany

    Peter Riederer

Authors
  1. Ana Knezovic
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  2. Jelena Osmanovic-Barilar
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  3. Marija Curlin
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  4. Patrick R. Hof
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  5. Goran Simic
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  6. Peter Riederer
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  7. Melita Salkovic-Petrisic
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Correspondence to Melita Salkovic-Petrisic.

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Knezovic, A., Osmanovic-Barilar, J., Curlin, M. et al. Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer’s disease. J Neural Transm 122, 577–592 (2015). https://doi.org/10.1007/s00702-015-1394-4

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  • DOI: https://doi.org/10.1007/s00702-015-1394-4

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