, Volume 10, Issue 6, pp 695–710

The difference in gliosis induced by β-amyloid and Tau treatments in astrocyte cultures derived from senescence accelerated and normal mouse strains

  • Lanhai Lü
  • Ying T. Mak
  • Marong Fang
  • David T. Yew
Research Article


Astrocytes react to various neurodegenerative insults rapidly and undergo changes known as gliosis or astrogliosis. In Alzheimer’s disease (AD), a wall of reactive astrocytes surrounds senile plaques of β-amyloid (Aβ) and might play an important role in clearing of Aβ. AD is neuropathologically characterized by the co-existence of two pathological structures, senile plaques and neurofibrillary tangles composed of Aβ and Tau protein respectively. However, the molecular mechanisms underlie astrogliosis and increased expressions of GFAP and other astrogliosis markers are poorly understood. Since AD is age related, the aim of this study is to compare the gliosis of aging prone astrocytes cultured from senescence-accelerated mice and astrocytes from normal mice in response to Aβ and Tau treatment. Our results demonstrated that the aging prone astrocytes have showed larger degree of gliosis than normal astrocytes. Since reactive astrocytes had less ability to support co-cultured neurons as compared with control astrocytes. Therefore, it is likely that aging prone astrocytes might contribute to cell loss or dysfunction associated with insults in AD. In other words, aging prone astrocytes might have decreased ability than normal astrocytes to protect or prevent neuronal dysfunction in AD pathology. In addition, further AD related studies should use aging prone astrocytes instead of normal astrocytes.


Astrogliosis Alzheimer’s disease Aging prone Astrocyte Neurodegenerative insult 


  1. Arnold SE, Lee VM, Gur RE, Trojanowski JQ (1991) Abnormal expression of two microtubule-associated proteins (MAP2 and MAP5) in specific subfields of the hippocampal formation in schizophrenia. Proc Natl Acad Sci USA 88:10850–10854. doi:10.1073/pnas.88.23.10850 CrossRefPubMedGoogle Scholar
  2. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259. doi:10.1007/BF00308809 CrossRefPubMedGoogle Scholar
  3. Burbach GJ, Dehn D, Del Turco D, STaufenbiel M, Deller T (2004) Laser microdissection reveals regional and cellular differences in GFAP mRNA upregulation following brain injury, axonal denervation, and amyloid plaque deposition. Glia 48:76–84. doi:10.1002/glia.20057 CrossRefPubMedGoogle Scholar
  4. Campbell RL, Bruce RD (1981) Comparative dermatotoxicology I direct comparison of rabbit and human primary skin irritation responses to isopropylmyristate. Toxicol Appl Pharmacol 59:555–563. doi:10.1016/0041-008X(81)90310-0 CrossRefPubMedGoogle Scholar
  5. Caputo CB, Sygowski LA, Scott CW, Sobel IR (1992) Role of Tau in the polymerization of peptides from beta-amyloid precursor protein. Brain Res 597:227–232. doi:10.1016/0006-8993(92)91478-W CrossRefPubMedGoogle Scholar
  6. Cardon LR, Bell JI (2001) Association study designs for complex diseases. Nat Rev Genet 2:91–99. doi:10.1038/35052543 CrossRefPubMedGoogle Scholar
  7. Chen M, Fernandez HL (2004) Stimulation of beta-amyloid precursor protein alpha-processing by phorbol ester involves calcium and calpain activation. Biochem Biophys Res Commun 316:332–340. doi:10.1016/j.bbrc.2004.02.052 CrossRefPubMedGoogle Scholar
  8. Chiarini A, Dal Pra I, Whitfield JF, Armato U (2006) The killing of neurons by beta-amyloid peptides, prions, and pro-inflammatory cytokines. Ital J Anat Embryol 111:221–246PubMedGoogle Scholar
  9. Cocchia D (1981) Immunocytochemical localization of S-100 protein in the brain of adult rat. An ultrastructural study. Cell Tissue Res 214:529–540. doi:10.1007/BF00233493 CrossRefPubMedGoogle Scholar
  10. Cotrina ML, Nedergaard M (2002) Astrocytes in the aging brain. J Neurosci Res 67:1–10. doi:10.1002/jnr.10121 CrossRefPubMedGoogle Scholar
  11. Dehmelt L, Halpain S (2004) Actin and microtubules in neurite initiation: are MAPs the missing link? J Neurobiol 58:18–33. doi:10.1002/neu.10284 CrossRefPubMedGoogle Scholar
  12. Dehmelt L, Halpain S (2005) The MAP2/Tau family of microtubule-associated proteins. Genome Biol 6:204Google Scholar
  13. DeWitt DA, Perry G, Cohen M, Doller C, Silver J (1998) Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer’s disease. Exp Neurol 149:329–355. doi:10.1006/exnr.1997.6738 CrossRefPubMedGoogle Scholar
  14. Eng LF, Ghirnikar RS (1994) GFAP and astrogliosis. Brain Pathol 4:229–237. doi:10.1111/j.1750-3639.1994.tb00838.x CrossRefPubMedGoogle Scholar
  15. Eng LF, Ghirnikar RS, Lee YL (2000) Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem Res 25:1439–1451. doi:10.1023/A:1007677003387 CrossRefPubMedGoogle Scholar
  16. Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward PJ (1990) Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 248:1122–1124. doi:10.1126/science.2111583 CrossRefPubMedGoogle Scholar
  17. Fauconneau B, Petegnief V, Sanfeliu C, Piriou A, Planas AM (2002) Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. J Neurochem 83:1338–1348. doi:10.1046/j.1471-4159.2002.01230.x CrossRefPubMedGoogle Scholar
  18. Finch CE (2003) Neurons, glia, and plasticity in normal brain aging. Neurobiol Aging 24(Suppl 1):S123–S127. doi:10.1016/S0197-4580(03)00051-4 CrossRefPubMedGoogle Scholar
  19. Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White III CL , Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA 86:7611–7615. doi:10.1073/pnas.86.19.7611 CrossRefPubMedGoogle Scholar
  20. Haglid KG, Yang Q, Hamberger A, Bergman S, Widerberg A, Danielsen N (1997) S-100beta stimulates neurite outgrowth in the rat sciatic nerve grafted with acellular muscle transplants. Brain Res 753:196–201. doi:10.1016/S0006-8993(96)01463-1 CrossRefPubMedGoogle Scholar
  21. Harada J, Sugimoto M (1999) Activation of caspase-3 in β-amyloid-induced apoptosis of cultured rat cortical neurons. Brain Res 842:311–323. doi:10.1016/S0006-8993(99)01808-9 CrossRefPubMedGoogle Scholar
  22. Holmes DJ (2003) F344. Rat Sci SAGE KE 36:as2Google Scholar
  23. Hung AY, Haass C, Nitsch RM, Qiu WQ, Citron M, Wurtman RJ, Growdon JH, Selkoe DJ (1993) Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. J Biol Chem 268:22959–22962PubMedGoogle Scholar
  24. Itoh Y, Esaki T, Shimoji K, Cook M, Law MJ, Kaufman E, Sokoloff L (2003) Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo. Proc Natl Acad Sci USA 100:4879–4884. doi:10.1073/pnas.0831078100 CrossRefPubMedGoogle Scholar
  25. Jolly-Tornetta C, Wolf BA (2000) Protein kinase C regulation of intracellular and cell surface amyloid precursor protein (APP) cleavage in CHO695 cells. Biochemistry 39:15282–15290. doi:10.1021/bi001723y CrossRefPubMedGoogle Scholar
  26. Kerokoski P, Soininen H, Pirttila ÈT (2001) β-amyloid (1–42) affects MTT reduction in astrocytes: implications for vesicular trafficking and cell functionality. Neurochem Int 38:127–134. doi:10.1016/S0197-0186(00)00071-1 CrossRefPubMedGoogle Scholar
  27. Kim C, Jang CH, Bang JH, Jung MW, Joo I, Kim SU, Mook-Jung I (2002) Amyloid precursor protein processing is separately regulated by protein kinase C and tyrosine kinase in human astrocytes. Neurosci Lett 324:185–188. doi:10.1016/S0304-3940(02)00217-3 CrossRefPubMedGoogle Scholar
  28. Kimura N, Negishi T, Ishii Y, Kyuwa S, Yoshikawa Y (2004) Astroglial responses against Abeta initially occur in cerebral primary cortical cultures: species differences between rat and cynomolgus monkey. Neurosci Res 49:339–346. doi:10.1016/j.neures.2004.03.010 CrossRefPubMedGoogle Scholar
  29. Kimura N, Ishii Y, Suzaki S, Negishi T, Kyuwa S, Yoshikawa Y (2007) Abeta upregulates and colocalizes with LGI3 in cultured rat astrocytes. Cell Mol Neurobiol 27:335–350. doi:10.1007/s10571-006-9127-8 CrossRefPubMedGoogle Scholar
  30. Kuperstein F, Reiss N, Koudinova N, Yavin E (2001) Biphasic modulation of protein kinase C and enhanced cell toxicity by amyloid beta peptide and anoxia in neuronal cultures. J Neurochem 76:758–767. doi:10.1046/j.1471-4159.2001.00037.x CrossRefPubMedGoogle Scholar
  31. Lace GL, Wharton SB, Ince PG (2007) A brief history of tau: the evolving view of the microtubule-associated protein tau in neurodegenerative diseases. Clin Neuropathol 26:43–58PubMedGoogle Scholar
  32. Lelovas PP, Xanthos TT, Thoma SE, Lyritis GP, Dontas IA (2008) The laboratory rat as an animal model for osteoporosis research. Comp Med 58:424–430PubMedGoogle Scholar
  33. Li Y, Wang J, Sheng JG, Liu L, Barger SW, Jones RA, Van Eldik LJ, Mrak RE, Griffin WS (1998) S100 beta increases levels of beta-amyloid precursor protein and its encoding mRNA in rat neuronal cultures. J Neurochem 71:1421–1428PubMedCrossRefGoogle Scholar
  34. Lü L, Li J, Yew DT, Rudd JA, Mak YT (2008) Oxidative stress on the astrocytes in culture derived from a senescence accelerated mouse strain. Neurochem Int 52:282–289. doi:10.1016/j.neuint.2007.06.016 CrossRefPubMedGoogle Scholar
  35. Luo Y, Hawver DB, Iwasaki K, Sunderland T, Roth GS, Wolozin B (1997) Physiological levels of beta-amyloid peptide stimulate protein kinase C in PC12 cells. Brain Res 769:287–295. doi:10.1016/S0006-8993(97)00718-X CrossRefPubMedGoogle Scholar
  36. Mak YT, Chan WY, Lam WP, Yew DT (2006) Immunohistological evidences of Ginkgo biloba extract altering Bax to Bcl-2 expression ratio in the hippocampus and motor cortex of senescence accelerated mice. Microsc Res Tech 69:601–605. doi:10.1002/jemt.20322 CrossRefPubMedGoogle Scholar
  37. Marshak DR (1990) S100 beta as a neurotrophic factor. Prog Brain Res 86:169–181. doi:10.1016/S0079-6123(08)63175-1 CrossRefPubMedGoogle Scholar
  38. Matsunaga W, Shirokawa T, Isobe K (2003) Specific uptake of Abeta1–40 in rat brain occurs in astrocyte, but not in microglia. Neurosci Lett 342:129–131. doi:10.1016/S0304-3940(03)00240-4 CrossRefPubMedGoogle Scholar
  39. Miyazaki H, Okuma Y, Nomura J, Nagashima K, Nomura Y (2003) Age-related alterations in the expression of glial cell line-derived neurotrophic factor in the senescence-accelerated mouse brain. J Pharmacol Sci 92:28–34. doi:10.1254/jphs.92.28 CrossRefPubMedGoogle Scholar
  40. Monnerie H, Esquenazi S, Shashidhara S, Le Roux PD (2005) Beta-amyloid-induced reactive astrocytes display altered ability to support dendrite and axon growth from mouse cerebral cortical neurons in vitro. Neurol Res 27:525–532. doi:10.1179/016164105X40020 CrossRefPubMedGoogle Scholar
  41. Nguyen PK, Smith AL, Reynolds KJ (2008) A literature review of different pressure ulcer models from 1942–2005 and the development of an ideal animal model. Australas Phys Eng Sci Med 31:223–225PubMedCrossRefGoogle Scholar
  42. Nishikawa T, Takahashi JA, Fujibayashi Y, Fujisawa H, Zhu B, Nishimura Y, Ohnishi K, Higuchi K, Hashimoto N, Hosokawa M (1998) An early stage mechanism of the age-associated mitochondrial dysfunction in the brain of SAMP8 mice; an age-associated neurodegeneration animal model. Neurosci Lett 254:69–72. doi:10.1016/S0304-3940(98)00646-6 CrossRefPubMedGoogle Scholar
  43. Peña LA, Brecher CW, Marshak DR (1995) beta-Amyloid regulates gene expression of glial trophic substance S100 beta in C6 glioma and primary astrocyte cultures. Brain Res Mol Brain Res 34:118–126. doi:10.1016/0169-328X(95)00145-I CrossRefPubMedGoogle Scholar
  44. Pertusa M, Garcia-Matas S, Rodriguez-Farre E, Sanfeliu C, Cristofol R (2007) Astrocytes aged in vitro show a decreased neuroprotective capacity. J Neurochem 101:794–805. doi:10.1111/j.1471-4159.2006.04369.x CrossRefPubMedGoogle Scholar
  45. Poon HF, Castegna A, Farr SA, Thongboonkerd V, Lynn BC, Banks WA, Morley JE, Klein JB, Butterfield DA (2004) Quantitative proteomics analysis of specific protein expression and oxidative modification in aged senescence-accelerated-prone 8 mice brain. Neuroscience 126:915–926. doi:10.1016/j.neuroscience.2004.04.046 CrossRefPubMedGoogle Scholar
  46. Praticò D (2008) Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol Sci 29:609–615. doi:10.1016/ CrossRefPubMedGoogle Scholar
  47. Radde R, Duma C, Goedert M, Jucker M (2008) The value of incomplete mouse models of Alzheimer’s disease. Eur J Nucl Med Mol Imaging 35(Suppl 1):S70–S74. doi:10.1007/s00259-007-0704-y CrossRefPubMedGoogle Scholar
  48. Rall DP (1995) Can laboratory animal carcinogenicity studies predict cancer in exposed children? Environ Health Perspect 103(Suppl 6):173–175. doi:10.2307/3432370 CrossRefPubMedGoogle Scholar
  49. Robinson MK, Cohen C, e Ade B, Ponec M, Whittle E, Fentem JH (2002) Non-animal testing strategies for assessment of the skin corrosion and skin irritation potential of ingredients and finished products. Food Chem Toxicol 40:573–592. doi:10.1016/S0278-6915(02)00005-4 CrossRefPubMedGoogle Scholar
  50. Salinero O, Moreno-Flores MT, Ceballos ML, Wandosell F (1997) beta-Amyloid peptide induced cytoskeletal reorganization in cultured astrocytes. J Neurosci Res 47:216–223. doi:10.1002/(SICI)1097-4547(19970115)47:2<216::AID-JNR10>3.0.CO;2-0 CrossRefPubMedGoogle Scholar
  51. Sánchez-Alvarez R, Tabernero A, Medina JM (2004) Endothelin-1 stimulates the translocation and upregulation of both glucose transporter and hexokinase in astrocytes: relationship with gap junctional communication. J Neurochem 89:703–714. doi:10.1046/j.1471-4159.2004.02398.x CrossRefPubMedGoogle Scholar
  52. Selkoe DJ, Yamazaki T, Citron M, Podlisny MB, Koo EH, Teplow DB, Haass C (1996) The role of APP processing and trafficking pathways in the formation of amyloid beta-protein. Ann N Y Acad Sci 777:57–64. doi:10.1111/j.1749-6632.1996.tb34401.x CrossRefPubMedGoogle Scholar
  53. Sjögren M, Davidsson P, Gottfries J, Vanderstichele H, Edman A, Vanmechelen E, Wallin A, Blennow K (2001) The cerebrospinal fluid levels of Tau, growth-associated protein-43 and soluble amyloid precursor protein correlate in Alzheimer’s disease, reflecting a common pathophysiological process. Dement Geriatr Cogn Disord 12:257–264. doi:10.1159/000051268 CrossRefPubMedGoogle Scholar
  54. Smith MA, Siedlak SL, Richey PL, Mulvihill P, Ghiso J, Frangione B, Tagliavini F, Giaccone G, Bugiani O, Praprotnik D, Kalaria RN, Perry G (1995) Tau protein directly interacts with the amyloid beta-protein precursor: implications for Alzheimer’s disease. Nat Med 1:365–369. doi:10.1038/nm0495-365 CrossRefPubMedGoogle Scholar
  55. Takeda T, Hosokawa M, Higuchi K (1991) Senescence-accelerated mouse (SAM): a novel murine model of accelerated senescence. J Am Geriatr Soc 39:911–919PubMedGoogle Scholar
  56. Takuma K, Baba A, Matsuda T (2004) Astrocyte apoptosis: implications for neuroprotection. Prog Neurobiol 72:111–127. doi:10.1016/j.pneurobio.2004.02.001 CrossRefPubMedGoogle Scholar
  57. Tiu SC, Chan WY, Heizmann CW, Schäfer BW, Shu SY, Yew DT (2000) Differential expression of S100B and S100A6(1) in the human fetal and aged cerebral cortex. Brain Res Dev Brain Res 119:159–168. doi:10.1016/S0165-3806(99)00151-0 CrossRefPubMedGoogle Scholar
  58. Wagner KU (2004) Models of breast cancer: quo vadis, animal modeling? Breast Cancer Res 6:31–38. doi:10.1186/bcr723 CrossRefPubMedGoogle Scholar
  59. Wai MS, Liang Y, Shi C, Cho EY, Kung HF, Yew DT (2008) Co-localization of hyperphosphorylated tau and caspases in the brainstem of Alzheimer’s disease patients. Biogerontology. doi:10.1007/s10522-008-9189-8 PubMedGoogle Scholar
  60. Wilson JE (2003) Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol 206:2049–2057. doi:10.1242/jeb.00241 CrossRefPubMedGoogle Scholar
  61. Wood CE, Usborne AL, Starost MF, Tarara RP, Hill LR, Wilkinson LM, Geisinger KR, Feiste EA, Cline JM (2006) Hyperplastic and neoplastic lesions of the mammary gland in macaques. Vet Pathol 43:471–483. doi:10.1354/vp.43-4-471 CrossRefPubMedGoogle Scholar
  62. Wu Y, Zhang AQ, Yew DT (2005) Age related changes of various markers of astrocytes in senescence-accelerated mice hippocampus. Neurochem Int 46:565–574. doi:10.1016/j.neuint.2005.01.002 CrossRefPubMedGoogle Scholar
  63. 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 9:453–457. doi:10.1038/nm838 CrossRefPubMedGoogle Scholar
  64. Xu K, Malouf AT, Messing A, Silver J (1999) Glial fibrillary acidic protein is necessary for mature astrocytes to react to beta-amyloid. Glia 25:390–403. doi:10.1002/(SICI)1098-1136(19990215)25:4<390::AID-GLIA8>3.0.CO;2-7 CrossRefPubMedGoogle Scholar
  65. Yew DT, Ping Li W, Liu WK (2004) Fas and activated caspase 8 in normal, Alzheimer and multiple infarct brains. Neurosci Lett 367:113–117. doi:10.1016/j.neulet.2004.05.091 CrossRefPubMedGoogle Scholar
  66. Zhou S, Kestell P, Paxton JW (2002) Predicting pharmacokinetics and drug interactions in patients from in vitro and in vivo models: the experience with 5, 6-dimethylxanthenone-4-acetic acid (DMXAA), an anti-cancer drug eliminated mainly by conjugation. Drug Metab Rev 34:751–790. doi:10.1081/DMR-120015693 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Lanhai Lü
    • 1
  • Ying T. Mak
    • 2
  • Marong Fang
    • 3
  • David T. Yew
    • 2
  1. 1.Department of Anatomy, School of MedicineSun Yat-sen UniversityGuangzhouPeople’s Republic of China
  2. 2.Department of AnatomyChinese University of Hong KongHong KongChina
  3. 3.Institute of Cell BiologyMedical College of Zhejiang UniversityHangzhou, ZhejiangPeople’s Republic of China

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