Skip to main content

Advertisement

SpringerLink
Log in

Autophagy is involved in oral rAAV/Aβ vaccine-induced Aβ clearance in APP/PS1 transgenic mice

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

The imbalance between ß-amyloid (Aß) generation and clearance plays a fundamental role in the pathogenesis of Alzheimer’s disease (AD). The sporadic form of AD is characterized by an overall impairment in Aß clearance. Immunotherapy targeting Aß clearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Aß clearance. We previously reported that oral vaccination with a recombinant AAV/Aß vaccine increased the clearance of Aß from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with rAAV/Aß decreased the p62 level and up-regulated the LC3B-II/LC3B-I ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/mTOR pathway may account for autophagy enhancement. We also found increased anti-Aß antibodies in the sera of APP/PS1 mice with oral vaccination, accompanied by elevation of complement factors C1q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Aß clearance, and modulating the autophagy pathway may be an important strategy for AD prevention and intervention.

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

Similar content being viewed by others

References

  1. Citron M. Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov 2010, 9: 387–398.

    Article  CAS  PubMed  Google Scholar 

  2. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002, 297: 353–356.

    Article  CAS  PubMed  Google Scholar 

  3. Krstic D, Knuesel I. Deciphering the mechanism underlying late-onset alzheimer disease. Nat Rev Neurol 2013, 9: 25–34.

    Article  CAS  PubMed  Google Scholar 

  4. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 2010, 330: 1774.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999, 400: 173–177.

    Article  CAS  PubMed  Google Scholar 

  6. Wisniewski T, Goni F. Immunotherapy for Alzheimer’s disease. Biochem Pharmacol 2014, 88: 499–507.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Wisniewski T. Active immunotherapy for Alzheimer’s disease. Lancet Neurol 2012, 11: 571–572.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mildto- moderate Alzheimer’s disease. N Engl J Med 2014, 370: 322–333.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-tomoderate Alzheimer’s disease. N Engl J Med 2014, 370: 311–321.

    Article  CAS  PubMed  Google Scholar 

  10. Hara H, Monsonego A, Yuasa K, Adachi K, Xiao X, Takeda S, et al. Development of a safe oral Abeta vaccine using recombinant adeno-associated virus vector for Alzheimer’s disease. J Alzheimers Dis 2004, 6: 483–488.

    CAS  PubMed  Google Scholar 

  11. Mouri A, Noda Y, Hara H, Mizoguchi H, Tabira T, Nabeshima T. Oral vaccination with a viral vector containing Abeta cDNA attenuates age-related Abeta accumulation and memory deficits without causing inflammation in a mouse Alzheimer model. FASEB J 2007, 21: 2135–2148.

    Article  CAS  PubMed  Google Scholar 

  12. Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 2014, 112: 24–49.

    Article  CAS  PubMed  Google Scholar 

  13. Wong Y C, Holzbaur EL. Autophagosome dynamics in neurodegeneration at a glance. J Cell Sci 2015, 128: 1259–1267.

    Article  CAS  PubMed  Google Scholar 

  14. Chui DH, Tanahashi H, Ozawa K, Ikeda S, Checler F, Ueda O, et al. Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat Med 1999, 5: 560–564.

    Article  CAS  PubMed  Google Scholar 

  15. Steele J W, Gandy S. Latrepirdine (Dimebon(R)), a potential Alzheimer therapeutic, regulates autophagy and neuropathology in an Alzheimer mouse model. Autophagy 2013, 9: 617–618.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Shibuya Y, Chang CC, Huang LH, Bryleva EY, Chang TY. Inhibiting ACAT1/SOAT1 in microglia stimulates autophagymediated lysosomal proteolysis and increases Abeta1-42 clearance. J Neurosci 2014, 34: 14484–14501.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Kuballa P, Nolte WM, Castoreno AB, Xavier RJ. Autophagy and the immune system. Annu Rev Immunol 2012, 30: 611–646.

    Article  CAS  PubMed  Google Scholar 

  18. Saiga H, Nieuwenhuizen N, Gengenbacher M, Koehler A, Schuerer S, Moura- Alves P, et al. The recombinant BCG DeltaureC::hly vaccine targets the AIM2 inflammasome to induce autophagy and inflammation. J Infect Dis 2014.

    Google Scholar 

  19. Jackson WT. Viruses and the autophagy pathway. Virology 2015, 479–480: 450–456.

    Article  PubMed  Google Scholar 

  20. Dong X, Tian W, Wang G, Dong Z, Shen W, Zheng G, et al. Establishment of an AAV reverse infection-based array. PLoS One 2010, 5: e13479.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Tong Y, Yang H, Tian X, Wang H, Zhou T, Zhang S, et al. High manganese, a risk for Alzheimer’s disease: high manganese induces amyloid-beta related cognitive impairment. J Alzheimers Dis 2014, 42: 865–878.

    CAS  PubMed  Google Scholar 

  22. Carrera I, Etcheverria I, Fernandez-Novoa L, Lombardi VR, Lakshmana MK, Cacabelos R, et al. A comparative evaluation of a novel vaccine in APP/PS1 mouse models of Alzheimer’s disease. Biomed Res Int 2015, 2015: 807146.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ. Using mice to model Alzheimer’s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet 2014, 5: 88.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D, et al. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci U S A 2010, 107: 7036–7041.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Li W, Yu J, Liu Y, Huang X, Abumaria N, Zhu Y, et al. Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer’s disease mouse model. Mol Brain 2014, 7: 65.

    Google Scholar 

  26. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 1996, 2: 864–870.

    Article  CAS  PubMed  Google Scholar 

  27. Xian X, Liu T, Yu J, Wang Y, Miao Y, Zhang J, et al. Presynaptic defects underlying impaired learning and memory function in lipoprotein lipase-deficient mice. J Neurosci 2009, 29: 4681–4685.

    Article  CAS  PubMed  Google Scholar 

  28. Yu Y, Zhou L, Sun M, Zhou T, Zhong K, Wang H, et al. Xylocoside G reduces amyloid-beta induced neurotoxicity by inhibiting NF-kappaB signaling pathway in neuronal cells. J Alzheimers Dis 2012, 30: 263–275.

    CAS  PubMed  Google Scholar 

  29. Wisniewski T, Goni F. Immunotherapeutic approaches for Alzheimer’s disease. Neuron 2015, 85: 1162–1176.

    Article  CAS  PubMed  Google Scholar 

  30. Orsini F, DeBlasio D, Zangari R, Zanier ER, DeSimoni MG. Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis. Front Cell Neurosci 2014, 8: 380.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Eikelenboom P, Stam FC. Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol 1982, 57: 239–242.

    Article  CAS  PubMed  Google Scholar 

  32. Veerhuis R, Nielsen HM, Tenner AJ. Complement in the brain. Mol Immunol 2011, 48: 1592–1603.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Nilsson P, Saido TC. Dual roles for autophagy: degradation and secretion of Alzheimer’s disease Abeta peptide. Bioessays 2014, 36: 570–578.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Tramutola A, Triplett JC, DiDomenico F, Niedowicz DM, Murphy MP, Coccia R, et al. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. J Neurochem 2015, 133: 739–749.

    Article  CAS  PubMed  Google Scholar 

  35. Pujhari S, Kryworuchko M, Zakhartchouk AN. Role of phosphatidylinositol-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) signalling pathways in porcine reproductive and respiratory syndrome virus (PRRSV) replication. Virus Res 2014, 194: 138–144.

    Article  CAS  PubMed  Google Scholar 

  36. Jack CR, Jr., Knopman DS, Weigand SD, Wiste HJ, Vemuri P, Lowe V, et al. An operational approach to National Institute on Aging-Alzheimer’s Association criteria for preclinical Alzheimer disease. Ann Neurol 2012, 71: 765–775.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Hefti F, Goure WF, Jerecic J, Iverson KS, Walicke PA, Krafft GA. The case for soluble Abeta oligomers as a drug target in Alzheimer’s disease. Trends Pharmacol Sci 2013, 34: 261–266.

    Article  CAS  PubMed  Google Scholar 

  38. Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol 2010, 6: 108–119.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Zhang J, Wu X, Qin C, Qi J, Ma S, Zhang H, et al. A novel recombinant adeno-associated virus vaccine reduces behavioral impairment and beta-amyloid plaques in a mouse model of Alzheimer’s disease. Neurobiol Dis 2003, 14: 365–379.

    Article  CAS  PubMed  Google Scholar 

  40. Panza F, Solfrizzi V, Imbimbo BP, Tortelli R, Santamato A, Logroscino G. Amyloid-based immunotherapy for Alzheimer’s disease in the time of prevention trials: the way forward. Expert Rev Clin Immunol 2014, 10: 405–419.

    Article  CAS  PubMed  Google Scholar 

  41. Lambracht-Washington D, Qu BX, Fu M, Eagar TN, Stuve O, Rosenberg RN. DNA beta-amyloid(1-42) trimer immunization for Alzheimer disease in a wild-type mouse model. JAMA 2009, 302: 1796–1802.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Faria AM, Weiner HL. Oral to lerance: mechanisms and therapeutic applications. Adv Immunol 1999, 73: 153–264.

    Article  CAS  PubMed  Google Scholar 

  43. Pride M, Seubert P, Grundman M, Hagen M, Eldridge J, Black RS. Progress in the active immunotherapeutic approach to Alzheimer’s disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis 2008, 5: 194–196.

    Article  CAS  PubMed  Google Scholar 

  44. Wagner E, Frank MM. Therapeuti c potential of complement modulation. Nat Rev Drug Discov 2010, 9: 43–56.

    Article  CAS  PubMed  Google Scholar 

  45. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell 2007, 131: 1164–1178.

    Article  CAS  PubMed  Google Scholar 

  46. Aiyaz M, Lupton MK, Proitsi P, Powell JF, Lovestone S. Complement activation as a biomarker for Alzheimer’s disease. Immunobiology 2012, 217: 204–215.

    Article  CAS  PubMed  Google Scholar 

  47. Benoit ME, Hernandez MX, Dinh ML, Benavente F, Vasquez O, Tenner AJ. C1q-induced LRP1B and GPR6 proteins expressed early in Alzheimer disease mouse models, are essential for the C1q-mediated protection against amyloidbeta neurotoxicity. J Biol Chem 2013, 288: 654–665.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA. Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci 2008, 28: 6333–6341.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc Natl Acad Sci U S A 2002, 99: 10837–10842.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Liu YH, Giunta B, Zhou HD, Tan J, Wang YJ. Immunotherapy for Alzheimer disease: the challenge of adverse effects. Nat Rev Neurol 2012, 8: 465–469.

    CAS  PubMed  Google Scholar 

  51. Condello C, Yuan P, Schain A, Grutzen dler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Abeta42 hotspots around plaques. Nat Commun 2015, 6: 6176.

    Google Scholar 

  52. Zhang Y, Zou J, Yang J, Yao Z. 4Abeta 1-15-derived monoclonal antibody reduces more abeta burdens and neuroinflammation than homologous vaccine in APP/PS1 Mice. Curr Alzheimer Res 2015, 12: 384–397.

    Article  CAS  PubMed  Google Scholar 

  53. Guan X, Yang J, Gu H, Zou J, Yao Z. Im munotherapeutic efficiency of a tetravalent Abeta1-15 vaccine in APP/PS1 transgenic mice as mouse model for Alzheimer’s disease. Hum Vaccin Immunother 2013, 9: 1643–1653.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Lee CY, Landreth GE. The role of microg lia in amyloid clearance from the AD brain. J Neural Transm 2010, 117: 949–960.

    Article  CAS  PubMed  Google Scholar 

  55. Prokop S, Miller KR, Heppner FL. Microgl ia actions in Alzheimer’s disease. Acta Neuropathol 2013, 126: 461–477.

    Article  CAS  PubMed  Google Scholar 

  56. McGeer PL, Mc Geer EG. The amyloid cascade -inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 2013, 126: 479–497.

    Article  CAS  PubMed  Google Scholar 

  57. Lionaki E, Markaki M, Tavernarakis N. Auto phagy and ageing: insights from invertebrate model organisms. Ageing Res Rev 2013, 12: 413–428.

    Article  CAS  PubMed  Google Scholar 

  58. Martinez-Vicente M, Cuervo AM. Autophagy an d neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 2007, 6: 352–361.

    Article  CAS  PubMed  Google Scholar 

  59. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005, 64: 113–122.

    PubMed  Google Scholar 

  60. Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu WH, et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J Neurosci 2008, 28: 6926–6937.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Caccamo A, DePinto V, Messina A, Branca C, Od do S. Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer’s disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature. J Neurosci 2014, 34: 7988–7998.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 2012, 8: 445–544.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Perluigi M, DiDomenico F, Butterfield DA. mTOR signaling in aging and neurodegeneration: At the crossroad between metabolism dysfunction and impairment of autophagy. Neurobiol Dis 2015.

    Google Scholar 

  64. Heras-Sandoval D, Perez-Rojas JM, Hernandez-Damian J, Pedraza-Chaverri J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal 2014, 26: 2694–2701.

    Article  CAS  PubMed  Google Scholar 

  65. Zhu Z, Yan J, Jiang W, Yao XG, Chen J, Chen L, et al. Arctigenin effectively ameliorates memory impairment in Alzheimer’s disease model mice targeting both beta-amyloid production and clearance. J Neurosci 2013, 33: 13138–13149.

    Google Scholar 

  66. Valdor R, Macian F. Autophagy and the regulation o f the immune response. Pharmacol Res 2012, 66: 475–483.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Chen M, Hong MJ, Sun H, Wang L, Shi X, Gilbert BE, et al. Essential role for autophagy in the maintenance of immunological memory against influenza infection. Nat Med 2014, 20: 503–510.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Puleston DJ, Zhang H, Powell TJ, Lipina E, Sims S, P anse I, et al. Autophagy is a critical regulator of memory CD8(+) T cell formation. Elife 2014, 3.

    Google Scholar 

  69. Lin LT, Dawson PW, Richardson CD. Viral interactions with macroautophagy: a double-edged sword. Virology 2010, 402: 1–10.

    Article  CAS  PubMed  Google Scholar 

  70. Jack CR, Jr., Knopman DS, Jagust WJ, Shaw LM, Aisen P S, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 2010, 9: 119–128.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Jack CR, Jr., Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013, 12: 207–216.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Bloom GS. Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 2014, 71: 505–508.

    Article  PubMed  Google Scholar 

  73. Lemere CA. Developing novel immunogens for a safe and ef fective Alzheimer’s disease vaccine. Prog Brain Res 2009, 175: 83–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Sperling R, Mormino E, Johnson K. The evolution of precli nical Alzheimer’s disease: implications for prevention trials. Neuron 2014, 84: 608–622.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Yang C, Xiao S. New developments of clinical trial in immu notherapy for Alzheimer’s disease. Curr Pharm Biotechnol 2015, 16: 484–491.

    Article  CAS  PubMed  Google Scholar 

  76. Herzog C. Influence of parenteral administration routes and additional factors on vaccine safety and immunogenicity: a review of recent literature. Expert Rev Vaccines 2014, 13: 399–415.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neuroscience Research Institute & Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China

    He-Cheng Wang, Tao Zhang, Bolati Kuerban, Ying-Lan Jin & De-Hua Chui

  2. Center for Translational Research of Neurology Disease, First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China

    Weidong Le

  3. Division of Neurology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga, 849-8501, Japan

    Hideo Hara

  4. Department of Neurology, Peking University Third Hospital, Beijing, 100191, China

    Dong-Sheng Fan & De-Hua Chui

  5. Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, 400042, China

    Yan-Jiang Wang

  6. Department of Neurology, Graduate School of Medicine, Juntendo University, Tokyo, 113-0033, Japan

    Takeshi Tabira

Authors
  1. He-Cheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bolati Kuerban
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying-Lan Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Weidong Le
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hideo Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dong-Sheng Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan-Jiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takeshi Tabira
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. De-Hua Chui
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to De-Hua Chui.

Additional information

These authors contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, HC., Zhang, T., Kuerban, B. et al. Autophagy is involved in oral rAAV/Aβ vaccine-induced Aβ clearance in APP/PS1 transgenic mice. Neurosci. Bull. 31, 491–504 (2015). https://doi.org/10.1007/s12264-015-1546-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-015-1546-4

Keywords

Search

Navigation