Journal of Neural Transmission

, Volume 122, Issue 4, pp 577–592 | Cite as

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

  • Ana Knezovic
  • Jelena Osmanovic-Barilar
  • Marija Curlin
  • Patrick R. Hof
  • Goran Simic
  • Peter Riederer
  • Melita Salkovic-Petrisic
Neurology and Preclinical Neurological Studies - Original Article


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.


Alzheimer’s disease Streptozotocin Amyloid protein Tau protein Lysosomes Cognitive decline 



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.

Conflict of interest

The authors declare no conflict of interest.


  1. Agholme L, Hallbeck M, Benedikz E, Marcusson J, Kagedal K (2012) Amyloid-β secretion, generation, and lysosomal sequestration in response to proteasome inhibition: involvement of autophagy. J Alzheimers Dis 31:343–358PubMedGoogle Scholar
  2. Agrawal R, Mishra B, Tyagi E, Nath C, Shukla R (2010) Effect of curcumin on brain insulin receptors and memory functions in STZ (ICV) induced dementia model of rat. Pharmacol Res 61:247–252CrossRefPubMedGoogle Scholar
  3. Agrawal R, Tyagi E, Shukla R, Nath C (2011) Insulin receptor signaling in rat hippocampus: a study in STZ (ICV) induced memory deficit model. Eur Neuropsychopharmacol 21:261–273CrossRefPubMedGoogle Scholar
  4. Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H, Bugiani O, Del-Tredici K, Ferrer I, Gelpi E, Giaccone G, Graeber MB, Ince P, Kamphorst W, King A, Korkolopoulou P, Kovács GG, Larionov S, Meyronet D, Monoranu C, Parchi P, Patsouris E, Roggendorf W, Seilhean D, Tagliavini F, Stadelmann C, Streichenberger N, Thal DR, Wharton SB, Kretzschmar H (2008) Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium. Brain Pathol 18:484–496PubMedCentralPubMedGoogle Scholar
  5. Bales KR (2012) The value and limitations of transgenic mouse models used in drug discovery for Alzheimer’s disease: an update. Expert Opin Drug Discov 7:281–297CrossRefPubMedGoogle Scholar
  6. Blokland A, Jolles J (1993) Spatial learni ng deficit and reduced hippocampal ChAT activity in rats after an ICV injection of streptozotocin. Pharmacol Biochem Behav 44:491–494CrossRefPubMedGoogle Scholar
  7. Blondel O, Portha B (1989) Early appearance of in vivo insulin resistance in adult streptozotocin-injected rats. Diabete Metab 15:382–387PubMedGoogle Scholar
  8. Borroni B, Grassi M, Costanzi C, Archetti S, Caimi L, Padovani A (2006) APOE genotype and cholesterol levels in lewy body dementia and Alzheimer disease: investigating genotype-phenotype effect on disease risk. Am J Geriatr Psychiatry 14:1022–1031CrossRefPubMedGoogle Scholar
  9. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259CrossRefPubMedGoogle Scholar
  10. Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278CrossRefPubMedGoogle Scholar
  11. Braak H, Braak E (1997) Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging 18(4 Suppl):S85–S88CrossRefPubMedGoogle Scholar
  12. Braak E, Braak H, Mandelkow EM (1994) A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol 87:554–567CrossRefPubMedGoogle Scholar
  13. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404CrossRefPubMedCentralPubMedGoogle Scholar
  14. Buee L, Bussire T, Bue-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Rev 33:95–130CrossRefPubMedGoogle Scholar
  15. Cataldo AM, Hamilton DJ, Nixon RA (1994) Lysosomal abnormalities in degenerating neurons link neuronal compromise to senile plaque development in Alzheimer disease. Brain Res 640:68–80CrossRefPubMedGoogle Scholar
  16. Chen Y, Liang Z, Blanchard J, Dai CL, Sun S, Lee MH, Grundke-Iqbal I, Iqbal K, Liu F, Gong CX (2013) A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’s disease: similarities to and differences from the transgenic model (3xTg-AD mouse). Mol Neurobiol 47:711–725CrossRefPubMedCentralPubMedGoogle Scholar
  17. Cole GM, Huynh TV, Saitoh T (1989) Evidence for lysosomal processing of amyloid β-protein precursor in cultured cells. Neurochem Res 14:933–939CrossRefPubMedGoogle Scholar
  18. Correia SC, Santos RX, Perry G, Zhu X, Moreira PI, Smith MA (2011) Insulin-resistant brain state: the culprit in sporadic Alzheimer’s disease? Ageing Res Rev 10:264–273CrossRefPubMedCentralPubMedGoogle Scholar
  19. Correia SC, Santos RX, Santos MS, Casadesus G, Lamanna JC, Perry G, Smith MA, Moreira PI (2013) Mitochondrial abnormalities in a streptozotocin-induced rat model of sporadic Alzheimer’s disease. Curr Alzheimer Res 10:406–419CrossRefPubMedGoogle Scholar
  20. De Felice FG, Lourenco MV, Ferreira ST (2014) How does brain insulin resistance develop in Alzheimer’s disease? Alzheimers Dement 10(1 Suppl):S26–S32CrossRefPubMedGoogle Scholar
  21. de la Monte SM, Tong M (2014) Brain metabolic dysfunction at the core of Alzheimer’s disease. Biochem Pharmacol 88:548–559CrossRefPubMedGoogle Scholar
  22. de la Monte SM, Wands JR (2005) Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. J Alzheimer’s Dis 7:45–61Google Scholar
  23. Delacourte A, David JP, Sergeant N, Buée L, Wattez A, Vermersch P, Ghozali F, Fallet-Bianco C, Pasquier F, Lebert F, Petit H, Di Menza C (1999) The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology 52:1158–1165CrossRefPubMedGoogle Scholar
  24. Deng Y, Li B, Liu Y, Iqbal K, Grundke-Iqbal I, Gong CX (2009) Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: implication for Alzheimer’s disease. Am J Pathol 175:2089–2098CrossRefPubMedCentralPubMedGoogle Scholar
  25. Diana A, Simic G, Sinforiani E, Orrù N, Pichiri G, Bono G (2008) Mitochondria morphology and DNA content upon sublethal exposure to beta-amyloid1-42 peptide. Coll Antropol 32(Suppl. 1):51–58PubMedGoogle Scholar
  26. Frölich L, Blum-Degen D, Riederer P, Hoyer S (1999) A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer’s disease. Ann N Y Acad Sci 893:290–293CrossRefPubMedGoogle Scholar
  27. Giorgino F, Chen JH, Smith RJ (1992) Changes in tyrosine phosphorylation of insulin receptors and a 170,000 molecular weight nonreceptor protein in vivo in skeletal muscle of streptozotocin-induced diabetic rats: effects of insulin and glucose. Endocrinology 130:1433–1444PubMedGoogle Scholar
  28. Grieb P, Kryczka T, Fiedorowicz M, Frontczak-Baniewicz M, Walski M (2004) Expansion of the Golgi apparatus in rat cerebral cortex following intracerebroventricular injections of streptozotocin. Acta Neurobiol Exp (Wars) 64:481–489Google Scholar
  29. Grober E, Dickson D, Sliwinski MJ, Buschke H, Katz M, Crystal H, Lipton RB (1999) Memory and mental status correlates of modified Braak staging. Neurobiol Aging 20:573–579CrossRefPubMedGoogle Scholar
  30. Grünblatt E, Salkovic-Petrisic M, Osmanovic J, Riederer P, Hoyer S (2007) Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J Neurochem 101:757–770CrossRefPubMedGoogle Scholar
  31. Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2:a006270. doi: 10.1101/cshperspect.a006270 CrossRefPubMedCentralPubMedGoogle Scholar
  32. Hellweg R, Nitsch R, Hock C, Jaksch M, Hoyer S (1992) Nerve growth factor and choline acetyltransferase activity levels in the rat brain following experimental impairment of cerebral glucose and energy metabolism. J Neurosci Res 31:479–486CrossRefPubMedGoogle Scholar
  33. Heo JH, Lee SR, Lee ST, Lee KM, Oh JH, Jang DP, Chang KT, Cho ZH (2011) Spatial distribution of glucose hypometabolism induced by intracerebroventricular streptozotocin in monkeys. J Alzheimers Dis 25:517–523PubMedGoogle Scholar
  34. Hinrichs MH, Jalal A, Brenner B, Mandelkow E, Kumar S, Scholz T (2012) Tau protein diffuses along the microtubule lattice. J Biol Chem 287:38559–38568CrossRefPubMedCentralPubMedGoogle Scholar
  35. Hoyer S (2004) Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol 490:115–125CrossRefPubMedGoogle Scholar
  36. Hoyer S, Lannert H (2007) Long-term abnormalities in brain glucose/energy metabolism after inhibition of the neuronal insulin receptor: implication of tau-protein. J Neural Transm Suppl 72:195–202CrossRefPubMedGoogle Scholar
  37. Hurtado DE, Molina-Porcel L, Iba M, Aboagye AK, Paul SM, Trojanowski JQ, Lee VM (2010) Aβ accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model. Am J Pathol 177:1977–1988CrossRefPubMedCentralPubMedGoogle Scholar
  38. Javed H, Khan MM, Khan A, Vaibhav K, Ahmad A, Khuwaja G, Ahmed ME, Raza SS, Ashafaq M, Tabassum R, Siddiqui MS, El-Agnaf OM, Safhi MM, Islam F (2011) S-allyl cysteine attenuates oxidative stress associated cognitive impairment and neurodegeneration in mouse model of streptozotocin-induced experimental dementia of Alzheimer’s type. Brain Res 1389:133–142CrossRefPubMedGoogle Scholar
  39. Jellinger KA (2013) Pathology and pathogenesis of vascular cognitive impairment-a critical update. Front Aging Neurosci 5:17. doi: 10.3389/fnagi.2013.00017 CrossRefPubMedCentralPubMedGoogle Scholar
  40. Kadowaki T, Kasuga M, Akanuma Y, Ezaki O, Takaku F (1984) Decreased autophosphorylation of the insulin receptor-kinase in streptozotocin-diabetic rats. J Biol Chem 259:14208–14216PubMedGoogle Scholar
  41. Knobloch M, Konietzko U, Krebs DC, Nitsch RM (2007) Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol Aging 28:1297–1306CrossRefPubMedGoogle Scholar
  42. Kosaraju J, Gali CC, Khatwal RB, Dubala A, Chinni S, Holsinger RM, Madhunapantula VS, Muthureddy Nataraj SK, Basavan D (2013) Saxagliptin: a dipeptidyl peptidase-4 inhibitor ameliorates streptozotocin induced Alzheimer’s disease. Neuropharmacology 72:291–300CrossRefPubMedGoogle Scholar
  43. Kraska A, Santin MD, Dorieux O, Joseph-Mathurin N, Bourrin E, Petit F, Jan C, Chaigneau M, Hantraye P, Lestage P, Dhenain M (2012) In vivo cross-sectional characterization of cerebral alterations induced by intracerebroventricular administration of streptozotocin. PLoS One 7:e46196. doi: 10.1371/journal.pone.0046196 CrossRefPubMedCentralPubMedGoogle Scholar
  44. Lackovic Z, Salkovic M (1990) Streptozotocin and alloxan produce alterations in rat brain monoamines independently of pancreatic beta cells destruction. Life Sci 46:49–54CrossRefPubMedGoogle Scholar
  45. Lannert H, Hoyer S (1998) Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 112:1199–1208CrossRefPubMedGoogle Scholar
  46. Lee JH, Olichney JM, Hansen LA, Hofstetter CR, Thal LJ (2000) Small concomitant vascular lesions do not influence rates of cognitive decline in patients with Alzheimer disease. Arch Neurol 57:1474–1479PubMedGoogle Scholar
  47. Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte S (2006) Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. J Alzheimer’s Dis 9:13–33Google Scholar
  48. Leuner K, Müller WE, Reichert AS (2012) From mitochondrial dysfunction to amyloid beta formation: novel insights into the pathogenesis of Alzheimer’s disease. Mol Neurobiol 46:186–193CrossRefPubMedGoogle Scholar
  49. Lithner CU, Hedberg MM, Nordberg A (2011) Transgenic mice as a model for Alzheimer’s disease. Curr Alzheimer Res 8:818–831CrossRefPubMedGoogle Scholar
  50. Lopez EM, Bell KF, Ribeiro-da-Silva A, Cuello AC (2004) Early changes in neurons of the hippocampus and neocortex in transgenic rats expressing intracellular human a-beta. J Alzheimers Dis 6:421–431PubMedGoogle Scholar
  51. Mayer G, Nitsch R, Hoyer S (1990) Effects of changes in peripheral and cerebral glucose metabolism on locomotor activity, learning and memory in adult male rats. Brain Res 532:95–100CrossRefPubMedGoogle Scholar
  52. McGowan E, Eriksen J, Hutton M (2006) A decade of modeling Alzheimer’s disease in transgenic mice. Trends Genet 22:281–289CrossRefPubMedGoogle Scholar
  53. Mitchell AJ (2009) CSF phosphorylated tau in the diagnosis and prognosis of mild cognitive impairment and Alzheimer’s disease: a meta-analysis of 51 studies. J Neurol Neurosurg Psychiatr 80:966–975CrossRefPubMedGoogle Scholar
  54. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kövari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381CrossRefPubMedCentralPubMedGoogle Scholar
  55. Nitsch R, Hoyer S (1991) Local action of the diabetogenic drug streptozotocin on glucose and energy metabolism in rat brain cortex. Neurosci Lett 128:199–202CrossRefPubMedGoogle Scholar
  56. Niwa K, Kazama K, Younkin SG, Carlson GA, Iadecola C (2002) Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein. Neurobiol Dis 9:61–68CrossRefPubMedGoogle Scholar
  57. Nixon RA (2007) Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci 120:4081–4091CrossRefPubMedGoogle Scholar
  58. Noble EP, Wurtman RJ, Axelrod J (1967) A simple and rapid method for injecting H3-norepinephrine into the lateral ventricle of the rat brain. Life Sci 6:281–291CrossRefPubMedGoogle Scholar
  59. Osmanovic Barilar J, Knezovic A, Grünblatt E, Riederer P, Salkovic-Petrisic M (2014) 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. doi: 10.1007/s00702-014-1323-y [Epub ahead of print]
  60. Park SJ, Kim YH, Lee Y, Kim KM, Kim HS, Lee SR, Kim SU, Kim SH, Kim JS, Jeong KJ, Lee KM, Huh JW, Chang KT (2013) Selection of appropriate reference genes for RT-qPCR analysis in a streptozotocin-induced Alzheimer’s disease model of cynomolgus monkeys (Macaca fascicularis). PLoS One 8:e56034. doi: 10.1371/journal.pone.0056034 CrossRefPubMedCentralPubMedGoogle Scholar
  61. Pedersen WA, McMillan PJ, Klustad JJ, Leverenz JB, Craft S, Haynatzki GR (2006) Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 199:265–273CrossRefPubMedGoogle Scholar
  62. Pedrós I, Petrov D, Allgaier M, Sureda F, Barroso E, Beas-Zarate C, Auladell C, Pallàs M, Vázquez-Carrera M, Casadesús G, Folch J, Camins A (2014) Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer’s disease. Biochim Biophys Acta 1842:1556–1566CrossRefPubMedGoogle Scholar
  63. Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH (2010) Amyloid-independent mechanisms in Alzheimer’s disease pathogenesis. J Neurosci 30:14946–14954CrossRefPubMedCentralPubMedGoogle Scholar
  64. Pinton S, da Rocha JT, Gai BM, Nogueira CW (2011) Sporadic dementia of Alzheimer’s type induced by streptozotocin promotes anxiogenic behavior in mice. Behav Brain Res 223:1–6CrossRefPubMedGoogle Scholar
  65. Plaschke K, Hoyer S (1993) Action of the diabetogenic drug streptozotocin on glycolytic and glycogenolytic metabolism in adult rat brain cortex and hippocampus. Int J Dev Neurosci 11:477–483CrossRefPubMedGoogle Scholar
  66. Plaschke K, Kopitz J, Siegelin M, Schliebs R, Salkovic-Petrisic M, Riederer P, Hoyer S (2010) Insulin-resistant brain state after intracerebroventricular streptozotocin injection exacerbates Alzheimer-like changes in Tg2576 AbetaPP-overexpressing mice. J Alzheimers Dis 19:691–704PubMedGoogle Scholar
  67. Prickaerts J, Fahrig T, Blokland A (1999) Cognitive performance and biochemical markers in septum, hippocampus and striatum of rats after an i.c.v. injection of streptozotocin: a correlation analysis. Behav Brain Res 102:73–88CrossRefPubMedGoogle Scholar
  68. Prickaerts J, De Vente J, Honig W, Steinbusch H, Ittersum MMV, Blokland A, Steinbusch HW (2000) Nitric oxide synthase does not mediate neurotoxicity after an i.c.v. injection of streptozotocin in the rat. J Neural Transm 107:745–766CrossRefPubMedGoogle Scholar
  69. Rodrigues L, Dutra MF, Ilha J, Biasibetti R, Quincozes-Santos A, Leite MC, Marcuzzo S, Achaval M, Gonçalves CA (2010) Treadmill training restores spatial cognitive deficits and neurochemical alterations in the hippocampus of rats submitted to an intracerebroventricular administration of streptozotocin. J Neural Transm 117:1295–1305CrossRefPubMedGoogle Scholar
  70. Sabbagh MN, Cooper K, DeLange J, Stoehr JD, Thind K, Lahti T, Reisberg B, Sue L, Vedders L, Fleming SR, Beach TG (2010) Functional, global and cognitive decline correlates to accumulation of Alzheimer’s pathology in MCI and AD. Curr Alzheimer Res 7:280–286CrossRefPubMedCentralPubMedGoogle Scholar
  71. Salkovic M, Sabolic I, Lackovic Z (1995) Striatal dopaminergic D1 and D2 receptors after intracerebroventricular application of alloxan and streptozotocin in rat. J Neural Transm Gen Sect 100:137–145CrossRefPubMedGoogle Scholar
  72. Salkovic-Petrisic M, Hoyer S (2007) Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl 72:217–233CrossRefPubMedGoogle Scholar
  73. Salkovic-Petrisic M, Tribl F, Schmidt M, Hoyer S, Riederer P (2006) Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathway. J Neurochem 96:1005–1015CrossRefPubMedGoogle Scholar
  74. Salkovic-Petrisic M, Osmanovic J, Grünblatt E, Riederer P, Hoyer S (2009) Modeling sporadic alzheimer’s disease: the insulin resistant brain state generates multiple Long-term morphobiological abnormalities inclusive hyperphosphorylated tau protein and amyloid-β a synthesis. J Alzheimer’s Dis 18:729–750Google Scholar
  75. Salkovic-Petrisic M, Osmanovic-Barilar J, Brückner MK, Hoyer S, Arendt T, Riederer P (2011) Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer’s disease: a long-term follow up study. J Neural Transm 118:765–772CrossRefPubMedGoogle Scholar
  76. Salkovic-Petrisic M, Knezovic A, Hoyer S, Riederer P (2013) What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research. J Neural Transm 120:233–252CrossRefPubMedGoogle Scholar
  77. Santos TO, Mazucanti CH, Xavier GF, Torrão AS (2012) Early and late neurodegeneration and memory disruption after intracerebroventricular streptozotocin. Physiol Behav 107:401–413CrossRefPubMedGoogle Scholar
  78. Selkoe DJ (2001) Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis 3:75–80PubMedGoogle Scholar
  79. Sharma M, Gupta YK (2001) Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci 68:1021–1029CrossRefPubMedGoogle Scholar
  80. Shaw CA, Höglinger GU (2008) Neurodegenerative diseases: neurotoxins as sufficient etiologic agents? Neuromolecular Med 10:1–9CrossRefPubMedCentralPubMedGoogle Scholar
  81. Shingo AS, Kanabayashi T, Murase T, Kito S (2012) Cognitive decline in STZ-3 V rats is largely due to dysfunctional insulin signalling through the dentate gyrus. Behav Brain Res 229:378–383CrossRefPubMedGoogle Scholar
  82. Shingo AS, Kanabayashi T, Kito S, Murase T (2013) Intracerebroventricular administration of an insulin analogue recovers STZ-induced cognitive decline in rats. Behav Brain Res 241:105–111CrossRefPubMedGoogle Scholar
  83. Shoham S, Bejar C, Kovalev E, Weinstock M (2003) Intracerebroventricular injection of streptozotocin causes neurotoxicity to myelin that contributes to spatial memory deficits in rats. Exp Neurol 84:1043–1052CrossRefGoogle Scholar
  84. Shoham S, Bejar C, Kovalev E, Schorer-Apelbaum D, Weinstock M (2007) Ladostigil prevents gliosis, oxidative-nitrative stress and memory deficits induced by intracerebroventricular injection of streptozotocin in rats. Neuropharmacology 52:836–843CrossRefPubMedGoogle Scholar
  85. Simic G, Gnjidic M, Kostovic I (1998) Cytoskeletal changes as an alternative view on pathogenesis of Alzheimer’s disease. Period Biol 100:165–173Google Scholar
  86. Simic G, Stanic G, Mladinov M, Jovanov-Milosevic N, Kostovic I, Hof PR (2009) Does Alzheimer’s disease begin in the brainstem? Neuropathol Appl Neurobiol 35:532–554CrossRefPubMedCentralPubMedGoogle Scholar
  87. Smith MA, Drew KL, Nunomura A, Takeda A, Hirai K, Zhu X, Atwood CS, Raina AK, Rottkamp CA, Sayre LM, Friedland RP, Perry G (2002) Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs? Neurochem Int 40:527–531CrossRefPubMedGoogle Scholar
  88. Spruston N (2008) Pyramidal neurons: dendritic structure and synaptic integration. Nat Rev Neurosci 9:206–221CrossRefPubMedGoogle Scholar
  89. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J Alzheimers Dis 7:63–80PubMedGoogle Scholar
  90. Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cell of the rat pancreas. Physiol Res 50:537–546PubMedGoogle Scholar
  91. Tam JH, Pasternak SH (2012) Amyloid and Alzheimer’s disease: inside and out. Can J Neurol Sci 39:286–298CrossRefPubMedGoogle Scholar
  92. Thal DR, Ghebremedhin E, Rüb U, Yamaguchi H, Del Tredici K, Braak H (2002a) Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 61:282–293PubMedGoogle Scholar
  93. Thal DR, Rüb U, Orantes M, Braak H (2002b) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800CrossRefPubMedGoogle Scholar
  94. Thome J, Gsell W, Rösler M, Kornhuber J, Frölich L, Hashimoto E, Zielke B, Wiesbeck GA, Riederer P (1997) Oxidative-stress associated parameters (lactoferrin, superoxide dismutases) in serum of patients with Alzheimer’s disease. Life Sci 60:13–19CrossRefPubMedGoogle Scholar
  95. Uchihara T (2007) Silver diagnosis in neuropathology: principles, practice and revised interpretation. Acta Neuropathol 13:483–499CrossRefGoogle Scholar
  96. Völkel W, Sicilia T, Pähler A, Gsell W, Tatschner T, Jellinger K, Leblhuber F, Riederer P, Lutz WK, Götz ME (2006) Increased brain levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer’s disease. Neurochem Int 48:679–686CrossRefPubMedGoogle Scholar
  97. Wirths O, Multhaup G, Czech C, Blanchard V, Moussaoui S, Tremp G, Pradier L, Beyreuther K, Bayer TA (2001) Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice. Neurosci Lett 306:116–120CrossRefPubMedGoogle Scholar
  98. Zahs KR, Ashe KH (2010) ‘Too much good news’—are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer’s disease? Trends Neurosci 33:381–389CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Ana Knezovic
    • 1
  • Jelena Osmanovic-Barilar
    • 1
  • Marija Curlin
    • 2
  • Patrick R. Hof
    • 3
  • Goran Simic
    • 4
  • Peter Riederer
    • 5
  • Melita Salkovic-Petrisic
    • 1
  1. 1.Department of Pharmacology and Croatian Institute for Brain ResearchUniversity of Zagreb School of MedicineZagrebCroatia
  2. 2.Department of Histology and Croatian Institute for Brain ResearchUniversity of Zagreb School of MedicineZagrebCroatia
  3. 3.Fishberg Department of Neuroscience and Friedman Brain InstituteIcahn School of Medicine at Mount SinaiNew YorkUSA
  4. 4.Department of Neuroscience, Croatian Institute for Brain ResearchUniversity of Zagreb School of MedicineZagrebCroatia
  5. 5.Center of Psychic Health, Clinic and Policlinic for Psychiatry and PsychotherapyUniversity Hospital WürzburgWürzburgGermany

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