Neuroscience Bulletin

, Volume 34, Issue 6, pp 912–920 | Cite as

Early Activation of Astrocytes does not Affect Amyloid Plaque Load in an Animal Model of Alzheimer’s Disease

  • Dongpi Wang
  • Xiaoqin Zhang
  • Mingkai Wang
  • Dongming Zhou
  • Hongyu Pan
  • Qiang Shu
  • Binggui SunEmail author
Original Article


Astrocytes are closely associated with Alzheimer’s disease (AD). However, their precise roles in AD pathogenesis remain controversial. One of the reasons behind the different results reported by different groups might be that astrocytes were targeted at different stages of disease progression. In this study, by crossing hAPP (human amyloid precursor protein)-J20 mice with a line of GFAP-TK mice, we found that astrocytes were activated specifically at an early stage of AD before the occurrence of amyloid plaques, while microglia were not affected by this crossing. Activation of astrocytes at the age of 3–5 months did not affect the proteolytic processing of hAPP and amyloid plaque loads in the brains of hAPP-J20 mice. Our data suggest that early activation of astrocytes does not affect the deposition of amyloid β in an animal model of AD.


Astrocyte Alzheimer’s disease Amyloid plaque Mouse 



We thank Dr. Edward Koo (Department of Neuroscience, UCSD) for providing the CT-15 antibody. The 3D6 was provided by Janssen Research & Development (South San Francisco, CA). We are grateful to the Core Facilities of Zhejiang University Institute of Neuroscience for technical assistance. This work was supported by grants from the National Basic Research Development Program of China (2014CB964602), the National Natural Science Foundation of China (91132713 and 81400878), the Zhejiang Provincial Natural Science Foundation of China (LR13H090001), the Science and Technology Planning Project of Zhejiang Province, China (2017C03011), the ‘Double First-Rate’ Project Initiative, and Chinese Ministry of Education Project 111 Program (B13026).

Compliance with Ethical Standards

Conflict of interest

The authors disclosed that there was no conflict of interest.

Supplementary material

12264_2018_262_MOESM1_ESM.pdf (178 kb)
Supplementary material 1 (PDF 178 kb)


  1. 1.
    Musiek ES, Holtzman DM. Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nat Neurosci 2015, 18: 800–806.CrossRefGoogle Scholar
  2. 2.
    Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci 2016, 17: 5–21.CrossRefGoogle Scholar
  3. 3.
    Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell 2012, 148: 1204–1222.CrossRefGoogle Scholar
  4. 4.
    Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015, 14: 388–405.CrossRefGoogle Scholar
  5. 5.
    Pekny M, Pekna M, Messing A, Steinhauser C, Lee JM, Parpura V, et al. Astrocytes: a central element in neurological diseases. Acta Neuropathol 2016, 131: 323–345.CrossRefGoogle Scholar
  6. 6.
    Su F, Bai F, Zhang Z. Inflammatory cytokines and alzheimer’s disease: a review from the perspective of genetic polymorphisms. Neurosci Bull 2016, 32: 469–480.CrossRefGoogle Scholar
  7. 7.
    He L, Chen L, Li L. The TBK1-OPTN axis mediates crosstalk between mitophagy and the innate immune response: a potential therapeutic target for neurodegenerative diseases. Neurosci Bull 2017, 33: 354–356.CrossRefGoogle Scholar
  8. 8.
    Chung WS, Clarke LE, Wang GX, Stafford BK, Sher A, Chakraborty C, et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 2013, 504: 394–400.CrossRefGoogle Scholar
  9. 9.
    Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999, 97: 703–716.CrossRefGoogle Scholar
  10. 10.
    Garcia AD, Doan NB, Imura T, Bush TG, Sofroniew MV. GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat Neurosci 2004, 7: 1233–1241.CrossRefGoogle Scholar
  11. 11.
    Khakh BS, Sofroniew MV. Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 2015, 18: 942–952.CrossRefGoogle Scholar
  12. 12.
    Sofroniew MV. Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci 2015, 16: 249–263.CrossRefGoogle Scholar
  13. 13.
    Zuchero JB, Barres BA. Glia in mammalian development and disease. Development 2015, 142: 3805–3809.CrossRefGoogle Scholar
  14. 14.
    Osborn LM, Kamphuis W, Wadman WJ, Hol EM. Astrogliosis: an integral player in the pathogenesis of Alzheimer’s disease. Prog Neurobiol 2016, 144: 121–141.CrossRefGoogle Scholar
  15. 15.
    Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, et al. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 2003, 9: 453–457.CrossRefGoogle Scholar
  16. 16.
    Yin KJ, Cirrito JR, Yan P, Hu X, Xiao Q, Pan X, et al. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J Neurosci 2006, 26: 10939–10948.CrossRefGoogle Scholar
  17. 17.
    Kraft AW, Hu X, Yoon H, Yan P, Xiao Q, Wang Y, et al. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J 2013, 27: 187–198.CrossRefGoogle Scholar
  18. 18.
    Kamphuis W, Kooijman L, Orre M, Stassen O, Pekny M, Hol EM. GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer’s disease. Glia 2015, 63: 1036–1056.CrossRefGoogle Scholar
  19. 19.
    Furman JL, Sama DM, Gant JC, Beckett TL, Murphy MP, Bachstetter AD, et al. Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J Neurosci 2012, 32: 16129–16140.CrossRefGoogle Scholar
  20. 20.
    Jo S, Yarishkin O, Hwang YJ, Chun YE, Park M, Woo DH, et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med 2014, 20: 886–896.CrossRefGoogle Scholar
  21. 21.
    Li C, Zhao R, Gao K, Wei Z, Yin MY, Lau LT, et al. Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 2011, 8: 67–80.CrossRefGoogle Scholar
  22. 22.
    Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 2012, 4: 147ra111.CrossRefGoogle Scholar
  23. 23.
    Kanekiyo T, Xu H, Bu G. ApoE and Abeta in Alzheimer’s disease: accidental encounters or partners? Neuron 2014, 81: 740–754.CrossRefGoogle Scholar
  24. 24.
    Bush TG, Savidge TC, Freeman TC, Cox HJ, Campbell EA, Mucke L, et al. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 1998, 93: 189–201.CrossRefGoogle Scholar
  25. 25.
    Houades V, Koulakoff A, Ezan P, Seif I, Giaume C. Gap junction-mediated astrocytic networks in the mouse barrel cortex. J Neurosci 2008, 28: 5207–5217.CrossRefGoogle Scholar
  26. 26.
    Pannasch U, Freche D, Dallerac G, Ghezali G, Escartin C, Ezan P, et al. Connexin 30 sets synaptic strength by controlling astroglial synapse invasion. Nat Neurosci 2014, 17: 549–558.CrossRefGoogle Scholar
  27. 27.
    Chai H, Diaz-Castro B, Shigetomi E, Monte E, Octeau JC, Yu X, et al. Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 2017, 95: 531–549 e539.Google Scholar
  28. 28.
    Yang Y, Vidensky S, Jin L, Jie C, Lorenzini I, Frankl M, et al. Molecular comparison of GLT1 + and ALDH1L1 + astrocytes in vivo in astroglial reporter mice. Glia 2011, 59: 200–207.CrossRefGoogle Scholar
  29. 29.
    Suarez I, Bodega G, Fernandez B. Glutamine synthetase in brain: effect of ammonia. Neurochem Int 2002, 41: 123–142.CrossRefGoogle Scholar
  30. 30.
    Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000, 20: 4050–4058.CrossRefGoogle Scholar
  31. 31.
    Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, et al. Abeta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A 2013, 110: E2518–2527.CrossRefGoogle Scholar
  32. 32.
    Palop JJ, Jones B, Kekonius L, Chin J, Yu GQ, Raber J, et al. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer’s disease-related cognitive deficits. Proc Natl Acad Sci U S A 2003, 100: 9572–9577.CrossRefGoogle Scholar
  33. 33.
    Sun B, Zhou Y, Halabisky B, Lo I, Cho SH, Mueller-Steiner S, et al. Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer’s disease. Neuron 2008, 60: 247–257.CrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Dongpi Wang
    • 1
    • 2
    • 3
  • Xiaoqin Zhang
    • 1
    • 2
  • Mingkai Wang
    • 1
    • 2
  • Dongming Zhou
    • 1
    • 2
    • 3
  • Hongyu Pan
    • 1
    • 2
  • Qiang Shu
    • 3
  • Binggui Sun
    • 1
    • 2
    Email author
  1. 1.Department of Neurobiology, NHC and CAMS Key Laboratory of Medical NeurobiologyZhejiang University School of MedicineHangzhouChina
  2. 2.Department of Neurology of the First Affiliated Hospital, NHC and CAMS Key Laboratory of Medical NeurobiologyZhejiang University School of MedicineHangzhouChina
  3. 3.Children’s HospitalZhejiang University School of MedicineHangzhouChina

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