Skip to main content

Advertisement

SpringerLink
Log in

Intracerebroventricular Streptozotocin Exacerbates Alzheimer-Like Changes of 3xTg-AD Mice

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Alzheimer's disease (AD) involves several possible molecular mechanisms, including impaired brain insulin signaling and glucose metabolism. To investigate the role of metabolic insults in AD, we injected streptozotocin (STZ), a diabetogenic compound if used in the periphery, into the lateral ventricle of the 6-month-old 3xTg-AD mice and studied the cognitive function as well as AD-like brain abnormalities, such as tau phosphorylation and Aβ accumulation, 3–6 weeks later. We found that STZ exacerbated impairment of short-term and spatial reference memory in 3xTg-AD mice. We also observed an increase in tau hyperphosphorylation and neuroinflammation, a disturbance of brain insulin signaling, and a decrease in synaptic plasticity and amyloid β peptides in the brain after STZ treatment. The expression of 20 AD-related genes, including those involved in the processing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulin signaling, synaptic function, protein kinases, and apoptosis, was altered, suggesting that STZ disturbs multiple metabolic and cell signaling pathways in the brain. These findings provide experimental evidence of the role of metabolic insult in AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Arendt T (2009) Synaptic degeneration in Alzheimer's disease. Acta Neuropathol 118(1):167–179

    Article  PubMed  Google Scholar 

  2. Arluison M, Quignon M, Nguyen P, Thorens B, Leloup C, Penicaud L (2004) Distribution and anatomical localization of the glucose transporter 2 (GLUT2) in the adult rat brain–an immunohistochemical study. J Chem Neuroanat 28(3):117–136

    Article  CAS  PubMed  Google Scholar 

  3. Arnaud L, Robakis NK, Figueiredo-Pereira ME (2006) It may take inflammation, phosphorylation and ubiquitination to 'tangle' in Alzheimer's disease. Neurodegener Dis 3(6):313–319

    Article  PubMed  Google Scholar 

  4. Bensadoun A, Weinstein D (1976) Assay of proteins in the presence of interfering materials. Anal Biochem 70(1):241–250

    Article  CAS  PubMed  Google Scholar 

  5. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron 45(5):675–688

    Article  CAS  PubMed  Google Scholar 

  6. Blanchard J, Wanka L, Tung YC, Cardenas-Aguayo Mdel C, LaFerla FM, Iqbal K, Grundke-Iqbal I (2010) Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Abeta and tau pathologies in 3xTg-AD mice. Acta Neuropathol 120(5):605–621

    Article  CAS  PubMed  Google Scholar 

  7. Blondel O, Portha B (1989) Early appearance of in vivo insulin resistance in adult streptozotocin-injected rats. Diabete Metab 15(6):382–387

    CAS  PubMed  Google Scholar 

  8. Casadesus G, Moreira PI, Nunomura A, Siedlak SL, Bligh-Glover W, Balraj E, Petot G, Smith MA, Perry G (2007) Indices of metabolic dysfunction and oxidative stress. Neurochem Res 32(4–5):717–722

    Article  CAS  PubMed  Google Scholar 

  9. 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(2):711–725

    Article  CAS  PubMed  Google Scholar 

  10. Chen Y, Tian Z, Liang Z, Sun S, Dai CL, Lee MH, Laferla FM, Grundke-Iqbal I, Iqbal K, Liu F, Gong CX (2012) Brain gene expression of a sporadic (icv-STZ Mouse) and a familial mouse model (3xTg-AD Mouse) of Alzheimer's disease. PLoS One 7(12):e51432

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Clark RE, Zola SM, Squire LR (2000) Impaired recognition memory in rats after damage to the hippocampus. J Neurosci 20(23):8853–8860

    CAS  PubMed  Google Scholar 

  12. Clinton LK, Billings LM, Green KN, Caccamo A, Ngo J, Oddo S, McGaugh JL, LaFerla FM (2007) Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice. Neurobiol Dis 28(1):76–82

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 69(1):29–38

    Article  PubMed Central  PubMed  Google Scholar 

  14. de la Monte SM (2012) Brain insulin resistance and deficiency as therapeutic targets in Alzheimer's disease. Curr Alzheimer Res 9(1):35–66

    Article  PubMed Central  PubMed  Google Scholar 

  15. de Leon MJ, Ferris SH, George AE, Reisberg B, Christman DR, Kricheff II, Wolf AP (1983) Computed tomography and positron emission transaxial tomography evaluations of normal aging and Alzheimer's disease. J Cereb Blood Flow Metab 3(3):391–394

    Article  PubMed  Google Scholar 

  16. DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol 27(5):457–464

    Article  CAS  PubMed  Google Scholar 

  17. 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(5):2089–2098

    Article  CAS  PubMed  Google Scholar 

  18. Devi L, Alldred MJ, Ginsberg SD, Ohno M (2012) Mechanisms underlying insulin deficiency-induced acceleration of beta-amyloidosis in a mouse model of Alzheimer's disease. PLoS One 7(3):e32792

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Ennaceur A, Aggleton JP (1997) The effects of neurotoxic lesions of the perirhinal cortex combined to fornix transection on object recognition memory in the rat. Behav Brain Res 88(2):181–193

    Article  CAS  PubMed  Google Scholar 

  20. Ennaceur A, Neave N, Aggleton JP (1997) Spontaneous object recognition and object location memory in rats: the effects of lesions in the cingulate cortices, the medial prefrontal cortex, the cingulum bundle and the fornix. Exp Brain Res 113(3):509–519

    Article  CAS  PubMed  Google Scholar 

  21. Francis G, Martinez J, Liu W, Nguyen T, Ayer A, Fine J, Zochodne D, Hanson LR, Frey WH 2nd, Toth C (2009) Intranasal insulin ameliorates experimental diabetic neuropathy. Diabetes 58(4):934–945

    Article  CAS  PubMed  Google Scholar 

  22. Francis GJ, Martinez JA, Liu WQ, Xu K, Ayer A, Fine J, Tuor UI, Glazner G, Hanson LR, Frey WH 2nd, Toth C (2008) Intranasal insulin prevents cognitive decline, cerebral atrophy and white matter changes in murine type I diabetic encephalopathy. Brain 131(Pt 12):3311–3334

    Article  PubMed  Google Scholar 

  23. Gimenez-Llort L, Blazquez G, Canete T, Johansson B, Oddo S, Tobena A, LaFerla FM, Fernandez-Teruel A (2007) Modeling behavioral and neuronal symptoms of Alzheimer's disease in mice: a role for intraneuronal amyloid. Neurosci Biobehav Rev 31(1):125–147

    Article  CAS  PubMed  Google Scholar 

  24. Grunblatt 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(3):757–770

    Article  PubMed  Google Scholar 

  25. Heiss WD, Szelies B, Kessler J, Herholz K (1991) Abnormalities of energy metabolism in Alzheimer's disease studied with PET. Ann N Y Acad Sci 640:65–71

    CAS  PubMed  Google Scholar 

  26. Heneka MT, O'Banion MK (2007) Inflammatory processes in Alzheimer's disease. J Neuroimmunol 184(1–2):69–91

    Article  CAS  PubMed  Google Scholar 

  27. Ho L, Qin W, Pompl PN, Xiang Z, Wang J, Zhao Z, Peng Y, Cambareri G, Rocher A, Mobbs CV, Hof PR, Pasinetti GM (2004) Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J 18(7):902–904

    CAS  PubMed  Google Scholar 

  28. Hoyer S (2004) Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol 490(1–3):115–125

    Article  CAS  PubMed  Google Scholar 

  29. 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  CAS  PubMed  Google Scholar 

  30. Iqbal K, Wang X, Blanchard J, Liu F, Gong CX, Grundke-Iqbal I (2010) Alzheimer's disease neurofibrillary degeneration: pivotal and multifactorial. Biochem Soc Trans 38(4):962–966

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Janelsins MC, Mastrangelo MA, Oddo S, LaFerla FM, Federoff HJ, Bowers WJ (2005) Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice. J Neuroinflammation 2:23

    Article  PubMed Central  PubMed  Google Scholar 

  32. Jolivalt CG, Hurford R, Lee CA, Dumaop W, Rockenstein E, Masliah E (2010) Type 1 diabetes exaggerates features of Alzheimer's disease in APP transgenic mice. Exp Neurol 223(2):422–431

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM (2005) Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J Neurosci 25(39):8843–8853

    Article  CAS  PubMed  Google Scholar 

  34. Kloda A, Martinac B, Adams DJ (2007) Polymodal regulation of NMDA receptor channels. Channels (Austin) 1(5):334–343

    Google Scholar 

  35. Kopf D, Frolich L (2009) Risk of incident Alzheimer's disease in diabetic patients: a systematic review of prospective trials. J Alzheimers Dis 16(4):677–685

    PubMed  Google Scholar 

  36. Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2009) Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer's disease. J Neurochem 111(1):242–249

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2011) Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. J Pathol 225(1):54–62

    Article  CAS  PubMed  Google Scholar 

  38. Liu Y, Liu F, Iqbal K, Grundke-Iqbal I, Gong CX (2008) Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Lett 582(2):359–364

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Malinow R, Malenka RC (2002) AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 25:103–126

    Article  CAS  PubMed  Google Scholar 

  40. Marks DR, Tucker K, Cavallin MA, Mast TG, Fadool DA (2009) Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. J Neurosci 29(20):6734–6751

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Martinez-Coria H, Green KN, Billings LM, Kitazawa M, Albrecht M, Rammes G, Parsons CG, Gupta S, Banerjee P, LaFerla FM (2010) Memantine improves cognition and reduces Alzheimer's-like neuropathology in transgenic mice. Am J Pathol 176(2):870–880

    Article  CAS  PubMed  Google Scholar 

  42. Mastrangelo MA, Bowers WJ (2008) Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer's disease-related pathologies in male triple-transgenic mice. BMC Neurosci 9:81

    Article  PubMed Central  PubMed  Google Scholar 

  43. 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(1–2):95–100

    Article  CAS  PubMed  Google Scholar 

  44. Morris RG, Garrud P, Rawlins JN, O'Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297(5868):681–683

    Article  CAS  PubMed  Google Scholar 

  45. Mosconi L (2005) Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD. Eur J Nucl Med Mol Imaging 32(4):486–510

    Article  CAS  PubMed  Google Scholar 

  46. Nitsch R, Hoyer S (1991) Local action of the diabetogenic drug, streptozotocin, on glucose and energy metabolism in rat brain cortex. Neurosci Lett 128(2):199–202

    Article  CAS  PubMed  Google Scholar 

  47. Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM (2003) Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging 24(8):1063–1070

    Article  CAS  PubMed  Google Scholar 

  48. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39(3):409–421

    Article  CAS  PubMed  Google Scholar 

  49. Pei JJ, Gong CX, Iqbal K, Grundke-Iqbal I, Wu QL, Winblad B, Cowburn RF (1998) Subcellular distribution of protein phosphatases and abnormally phosphorylated tau in the temporal cortex from Alzheimer's disease and control brains. J Neural Trans 105(1):69–83

    Article  CAS  Google Scholar 

  50. Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14(3):149–167

    Article  CAS  PubMed  Google Scholar 

  51. Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, Herman M, Yu WH, Luchsinger JA, Wadzinski B, Duff KE, Takashima A (2007) Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci 27(50):13635–13648

    Article  CAS  PubMed  Google Scholar 

  52. 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(2):691–704

    CAS  PubMed  Google Scholar 

  53. 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(1–2):73–88

    Article  CAS  PubMed  Google Scholar 

  54. Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD, Frey WH 2nd, Craft S (2008) Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis 13(3):323–331

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Reiman EM, Caselli RJ, Chen K, Alexander GE, Bandy D, Frost J (2001) Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proc Natl Acad Sci U S A 98(6):3334–3339

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Rodrigues L, Biasibetti R, Swarowsky A, Leite MC, Quincozes-Santos A, Quilfeldt JA, Achaval M, Goncalves CA (2009) Hippocampal alterations in rats submitted to streptozotocin-induced dementia model are prevented by aminoguanidine. J Alzheimers Dis 17(1):193–202

    CAS  PubMed  Google Scholar 

  57. 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  CAS  PubMed  Google Scholar 

  58. Sargolini F, Roullet P, Oliverio A, Mele A (2003) Effects of intra-accumbens focal administrations of glutamate antagonists on object recognition memory in mice. Behav Brain Res 138(2):153–163

    Article  CAS  PubMed  Google Scholar 

  59. Selkoe DJ (2002) Alzheimer's disease is a synaptic failure. Science 298(5594):789–791

    Article  CAS  PubMed  Google Scholar 

  60. Shonesy BC, Thiruchelvam K, Parameshwaran K, Rahman EA, Karuppagounder SS, Huggins KW, Pinkert CA, Amin R, Dhanasekaran M, Suppiramaniam V (2012) Central insulin resistance and synaptic dysfunction in intracerebroventricular-streptozotocin injected rodents. Neurobiol Aging 33 (2):430 e435–418

    Google Scholar 

  61. Sims-Robinson C, Kim B, Rosko A, Feldman EL (2010) How does diabetes accelerate Alzheimer disease pathology? Nature reviews 6(10):551–559

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Smith GS, de Leon MJ, George AE, Kluger A, Volkow ND, McRae T, Golomb J, Ferris SH, Reisberg B, Ciaravino J et al (1992) Topography of cross-sectional and longitudinal glucose metabolic deficits in Alzheimer's disease. Pathophysiologic implications. Arch Neurol 49(11):1142–1150

    Article  CAS  PubMed  Google Scholar 

  63. Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50(6):537–546

    CAS  PubMed  Google Scholar 

  64. Tatebayashi Y, Iqbal K, Grundke-Iqbal I (1999) Dynamic regulation of expression and phosphorylation of tau by fibroblast growth factor-2 in neural progenitor cells from adult rat hippocampus. J Neurosci 19(13):5245–5254

    CAS  PubMed  Google Scholar 

  65. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30(4):572–580

    Article  CAS  PubMed  Google Scholar 

  66. Wang J, Dickson DW, Trojanowski JQ, Lee VM (1999) The levels of soluble versus insoluble brain Abeta distinguish Alzheimer's disease from normal and pathologic aging. Exp Neurol 158(2):328–337

    Article  CAS  PubMed  Google Scholar 

  67. Wang X, Zheng W, Xie JW, Wang T, Wang SL, Teng WP, Wang ZY (2010) Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model. Mol Neurodegener 5:46

    Article  PubMed Central  PubMed  Google Scholar 

  68. Weitz TM, Town T (2012) Microglia in Alzheimer's disease: it's all about context. Int J Alzheimers Dis 2012:314185

    PubMed Central  PubMed  Google Scholar 

  69. Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9(4):453–457

    Article  CAS  PubMed  Google Scholar 

  70. Wyss-Coray T, Rogers J (2012) Inflammation in Alzheimer disease—a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2(1):a006346

    Article  PubMed  Google Scholar 

  71. Yang Y, Ma D, Wang Y, Jiang T, Hu S, Zhang M, Yu X, Gong CX (2013) Intranasal insulin ameliorates tau hyperphosphorylation in a rat model of type 2 diabetes. J Alzheimers Dis 33(2):329–338

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank F.M. LaFerla of University of California, Irvine, for providing the breeding pairs of 3xTg-AD mouse, and Ms. J. Murphy for secretarial assistance. This work was supported in part by the New York State Office for People with Developmental Disabilities as well as grants from the National Institutes of Health (R01 AG027429 and R03 TW008123), the U.S. Alzheimer's Association (IIRG-10-170405 and IIRG-10-173154), the National Key Basic Research Program of China (2013CB530900), and the Wuhan Science and Technology Bureau, China (200960323132). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314-6399, USA

    Yanxing Chen, Zhu Tian, Julie Blanchard, Chun-ling Dai, Sonia Chalbot, Khalid Iqbal, Fei Liu & Cheng-Xin Gong

  2. Department of Neurology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China

    Yanxing Chen

  3. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, 430022, China

    Yanxing Chen & Zhihou Liang

  4. Department of Neurology, Tianjin First Center Hospital, Tianjin, 300192, China

    Zhu Tian

Authors
  1. Yanxing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhihou Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhu Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Julie Blanchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chun-ling Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sonia Chalbot
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Khalid Iqbal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cheng-Xin Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cheng-Xin Gong.

Additional information

This paper is dedicated to late Inge Grundke-Iqbal, Ph.D., who made seminal contributions to our understanding of neurofibrillary degeneration in Alzheimer's disease.

Y. Chen and Z. Liang contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 27 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, Y., Liang, Z., Tian, Z. et al. Intracerebroventricular Streptozotocin Exacerbates Alzheimer-Like Changes of 3xTg-AD Mice. Mol Neurobiol 49, 547–562 (2014). https://doi.org/10.1007/s12035-013-8539-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-013-8539-y

Keywords

Search

Navigation