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Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer’s disease: a long-term follow up study

  • Dementias - Original Article
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Abstract

Cerebral amyloid angiopathy is manifested as accumulation of amyloid β (Aβ) peptide in the wall of meningeal and cerebral arteries, arterioles and capillaries and is frequently found postmortem in sporadic Alzheimer’s disease (sAD) patients. It is difficult to assess when and how cerebral amyloid angiopathy develops and progresses in humans in vivo, which is why animal AD models are used. Streptozotocin-intracerebroventricularly (STZ-icv) treated rats have been recently proposed as the model of sAD which develops insulin resistant brain state preceding Aβ pathology development. Vascular Aβ deposits in the brain of STZ-icv-treated rats (3 months old at the time of icv treatment) were visualized by Thioflavine-S staining, Congo red staining and Aβ immunohistochemistry. Thioflavine-S and Congo red staining revealed diffuse congophilic deposits in the wall of meningeal and cortical blood vessels both 6 and 9 months after the STZ-icv treatment. Preliminary Aβ1-42 and Aβ1-16 immunohistochemistry experiments showed positive staining in blood vessels 3 and 9 months after the STZ-icv treatment, respectively. Results suggest that cerebral amyloid angiopathy observed 6 and 9 months after the STZ-icv treatment seems to be a continuation and progression of the amyloid pathology observed already 3 months following the STZ-icv treatment in this non-transgenic sAD animal model.

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References

  • 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 21:261–273

    Article  PubMed  CAS  Google Scholar 

  • Alafuzoff I, Thal DR, Arzberger T, Bogdanovic N, Al-Sarraj S, Bodi I, Boluda S, Bugiani O, Duyckaerts C, Gelpi E, Gentleman S, Giaccone G, Graeber M, Hortobagyi T, Höftberger R, Ince P, Ironside JW, Kavantzas N, King A, Korkolopoulou P, Kovács GG, Meyronet D, Monoranu C, Nilsson T, Parchi P, Patsouris E, Pikkarainen M, Revesz T, Rozemuller A, Seilhean D, Schulz-Schaeffer W, Streichenberger N, Wharton SB, Kretzschmar H (2009) Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium. Acta Neuropathol 117:309–320

    Article  PubMed  CAS  Google Scholar 

  • Attems J, Jellinger KA (2004) Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology—a pilot study. Acta Neuropathol 107:83–90

    Article  PubMed  Google Scholar 

  • Attems J, Jellinger KA, Lintner F (2005) Alzheimer’s disease pathology influences severity and topographical distribution of cerebral amyloid angiopathy. Acta Neuropathol 110:222–231

    Article  PubMed  Google Scholar 

  • Blokland A, Jolles J (1993) Spatial learning deficit and reduced hippocampal ChAT activity in rats after an ICV injection of streptozotocin. Pharmacol Biochem Behav 44:491–494

    Article  PubMed  CAS  Google Scholar 

  • Blokland A, Jolles J (1994) Behavioral and biochemical effects of an ICV injection of streptozotocin in old Lewis rats. Pharmacol Biochem Behav 47:833–837

    Article  PubMed  CAS  Google Scholar 

  • Blondel O, Portha B (1989) Early appearance of in vivo insulin resistance in adult streptozotocin-injected rats. Diabete Metab 15:382–387

    PubMed  CAS  Google Scholar 

  • Calhoun ME, Burgermeister P, Phinney AL, Stalder M, Tolnay M, Wiederhold KH, Abramowski D, Sturchler-Pierrat C, Sommer B, Staufenbiel M, Jucker M (1999) Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci USA 96:14088–14093

    Article  PubMed  CAS  Google Scholar 

  • 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 Alzheimers Dis 7:45–61

    PubMed  Google Scholar 

  • Domnitz SB, Robbins EM, Hoang AW, Garcia-Alloza M, Hyman BT, Rebeck GW, Greenberg SM, Bacskai BJ, Frosch MP (2005) Progression of cerebral amyloid angiopathy in transgenic mouse models of Alzheimer disease. J Neuropathol Exp Neurol 64:588–594

    PubMed  CAS  Google Scholar 

  • Duyckaerts C, Potier MC, Delatour B (2008) Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol 115:5–38

    Article  PubMed  Google Scholar 

  • Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118:5–36

    Article  PubMed  CAS  Google Scholar 

  • Frölich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheimer A, Turk A, Hoyer S, Zöchling R, Boissl KW, Jellinger K, Riederer P (1998) Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm 105:423–438

    Article  PubMed  Google Scholar 

  • Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP (2006) Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis 24:516–524

    Article  PubMed  CAS  Google Scholar 

  • Giorgino F, Chen JH, Smith RJ (1992) Changes in tyrosine phosphorylation of insulin receptors and a 170, 000 molecular weight non-receptor protein in vivo in skeletal muscle of streptozotocin-induced diabetic rats: effects of insulin and glucose. Endocrinology 130:1433–1444

    Article  PubMed  CAS  Google Scholar 

  • 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 101:757–770

    Article  PubMed  Google Scholar 

  • 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 31:479–486

    Article  PubMed  CAS  Google Scholar 

  • Hoyer S (1998) Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J Neural Transm 105:415–422

    Article  PubMed  CAS  Google Scholar 

  • Hoyer S (2004) Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol 490:115–125

    Article  PubMed  CAS  Google Scholar 

  • 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 72:195–202

    Article  PubMed  CAS  Google Scholar 

  • Jellinger KA (2002) Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 109:813–836

    Article  PubMed  CAS  Google Scholar 

  • 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 259:14208–142016

    PubMed  CAS  Google Scholar 

  • 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 112:1199–1208

    Article  PubMed  CAS  Google Scholar 

  • Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM (2006) Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. J Alzheimers Dis 9:13–33

    PubMed  CAS  Google Scholar 

  • 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 532:95–100

    Article  PubMed  CAS  Google Scholar 

  • Nishitomi K, Sakaguchi G, Horikoshi Y, Gray AJ, Maeda M, Hirata-Fukae C, Becker AG, Hosono M, Sakaguchi I, Minami SS, Nakajima Y, Li HF, Takeyama C, Kihara T, Ota A, Wong PC, Aisen PS, Kato A, Kinoshita N, Matsuoka Y (2006) BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. J Neurochem 99:1555–1563

    Article  PubMed  CAS  Google Scholar 

  • Nitsch R, Hoyer S (1991) Local action of the diabetogenic drug, streptozotocin, on glucose and energy metabolism in rat brain cortex. Neurosci Lett 128:199–202

    Article  PubMed  CAS  Google Scholar 

  • 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 6:281–291

    Article  PubMed  CAS  Google Scholar 

  • 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 11:477–483

    Article  PubMed  CAS  Google Scholar 

  • Robbins EM, Betensky RA, Domnitz SB, Purcell SM, Garcia-Alloza M, Greenberg C, Rebeck GW, Hyman BT, Greenberg SM, Frosch MP, Bacskai BJ (2006) Kinetics of cerebral amyloid angiopathy progression in a transgenic mouse model of Alzheimer disease. J Neurosci 26:365–371

    Article  PubMed  CAS  Google Scholar 

  • Rochet JC, Lansbury PT Jr (2000) Amyloid fibrillogenesis: themes and variations. Curr Opin Struct Biol 10:60–68

    Article  PubMed  CAS  Google Scholar 

  • Salkovic-Petrisic M, Hoyer S (2007) Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl 72:217–233

    Article  PubMed  CAS  Google Scholar 

  • 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 96:1005–1015

    Article  PubMed  CAS  Google Scholar 

  • 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 including hyperphosphorylated tau protein and amyloid-beta. J Alzheimers Dis 18:729–750

    PubMed  CAS  Google Scholar 

  • Schechter R, Whitmire J, Holtzelaw L, George M, Devaskar SU (1992) Developmental regulation of insulin in the mammalian central nervous system. Brain Res 582:27–37

    Article  PubMed  CAS  Google Scholar 

  • Schechter R, Beju D, Gaffney T, Schaefer F, Whetsell L (1996) Preproinsulin I and II mRNAs and insulin electron microscopic immuno-reaction are present within the fetal nervous system. Brain Res 736:16–27

    Article  PubMed  CAS  Google Scholar 

  • 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 Alzheimer’s Dis 7:63–80

    CAS  Google Scholar 

  • Stopa EG, Butala P, Salloway S, Johanson CE, Gonzalez L, Tavares R, Hovanesian V, Hulette CM, Vitek MP, Cohen RA (2008) Cerebral cortical arteriolar angiopathy, vascular beta-amyloid, smooth muscle actin, Braak stage, and APOE genotype. Stroke 39:814–821

    Article  PubMed  Google Scholar 

  • Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cell of the rat pancreas. Physiol Res 50:537–546

    PubMed  CAS  Google Scholar 

  • Thal DR, Capetillo-Zarate E, Larionov S, Staufenbiel M, Zurbruegg S, Beckmann N (2009) Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances. Neurobiol Aging 30:1936–1948

    Article  PubMed  CAS  Google Scholar 

  • Van Dorpe J, Smeijers L, Dewachter I, Nuyens D, Spittaels K, Van Den Haute C, Mercken M, Moechars D, Laenen I, Kuiperi C, Bruynseels K, Tesseur I, Loos R, Vanderstichele H, Checler F, Sciot R, Van Leuven F (2000) Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons. Am J Pathol 157:1283–1298

    Article  PubMed  Google Scholar 

  • Weller RO, Nicoll JA (2003) Cerebral amyloid angiopathy: pathogenesis and effects on the ageing and Alzheimer brain. Neurol Res 25:611–616

    Article  PubMed  Google Scholar 

  • Yamada M (2002) Risk factors for cerebral amyloid angiopathy in the elderly. Ann N Y Acad Sci 977:37–44

    Article  PubMed  Google Scholar 

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Acknowledgments

Supported by Deutscher Akademischer Austausch Dienst (project No. A/04/20017), and the Croatian Ministry of Science, Education and Sport (project No. 0108253). Special thanks to Mrs Bozica Hrzan for technical assistance.

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Correspondence to Melita Salkovic-Petrisic.

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Salkovic-Petrisic, M., Osmanovic-Barilar, J., Brückner, M.K. et al. Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer’s disease: a long-term follow up study. J Neural Transm 118, 765–772 (2011). https://doi.org/10.1007/s00702-011-0651-4

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  • DOI: https://doi.org/10.1007/s00702-011-0651-4

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