Journal of Neuroimmune Pharmacology

, Volume 7, Issue 3, pp 640–655 | Cite as

Efficacy of a Therapeutic Vaccine Using Mutated β-amyloid Sensitized Dendritic Cells in Alzheimer’s Mice

  • Zhongqiu Luo
  • Jialin Li
  • Neel R. Nabar
  • Xiaoyang Lin
  • Ge Bai
  • Jianfeng Cai
  • Shu-Feng Zhou
  • Chuanhai Cao
  • Jinhuan Wang


Despite FDA suspension of Elan’s AN-1792 amyloid beta (Aβ) vaccine in phase IIb clinical trials, the implications of this study are the guiding principles for contemporary anti-Aβ immunotherapy against Alzheimer’s disease (AD). AN-1792 showed promising results with regards to Aβ clearance and cognitive function improvement, but also exhibited an increased risk of Th1 mediated meningoencephalitis. As such, vaccine development has continued with an emphasis on eliciting a notable anti-Aβ antibody titer, while avoiding the unwanted Th1 pro-inflammatory response. Previously, we published the first report of an Aβ sensitized dendritic cell vaccine as a therapeutic treatment for AD in BALB/c mice. Our vaccine elicited an anti-Aβ titer, with indications that a Th1 response was not present. This study is the first to investigate the efficacy and safety of our dendritic cell vaccine for the prevention of AD in transgenic mouse models (PDAPP) for AD. We also used Immunohistochemistry to characterize the involvement of LXR, ABCA1, and CD45 in order to gain insight into the potential mechanisms through which this vaccine may provide benefit. The results indicate that (1) the use of mutant Aβ1-42 sensitized dendritic cell vaccine results in durable antibody production, (2) the vaccine provides significant benefits with regards to cognitive function without the global (Th1) inflammation seen in prior Aβ vaccines, (3) histological studies showed an overall decrease in Aβ burden, with an increase in LXR, ABCA1, and CD45, and (4) the beneficial results of our DC vaccine may be due to the LXR/ABCA1 pathway. In the future, mutant Aβ sensitized dendritic cell vaccines could be an efficacious and safe method for the prevention or treatment of AD that circumvents problems associated with traditional anti-Aβ vaccines.


Dendritic cell Vaccine Alzheimer’s disease Amyloid beta Peptide Immune system 



This research was supported by funds from key project of Tianjin Municipal Science and Technology Commission (09JCZDJC20200), as well as by the funds from key project of Tianjin Public Health Bureau (06KG09).

Conflicts of Interest

The authors declare no conflicts of interest.


  1. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000) Inflammation and Alzheimer's disease. In: Neurobiol Aging, vol 21. vol 3. United States, pp 383–421Google Scholar
  2. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6(8):916–919. doi: 10.1038/78682 PubMedCrossRefGoogle Scholar
  3. Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, Jenkins L, Millais SB, Donoghue S (2005) Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. In: Neurology, vol 64. vol 1. United States, pp 94–101. doi: 10.1212/01.wnl.0000148604.77591.67
  4. Birmingham K, Frantz S (2002) Set back to Alzheimer vaccine studies. In: Nat Med, vol 8. vol 3. United States, pp 199–200. doi: 10.1038/nm0302-199b
  5. Bryan KJ, Lee H, Perry G, Smith MA, Casadesus G (2009) Transgenic mouse models of Alzheimer's disease: behavioral testing and considerations methods of behavior analysis in neuroscience. Taylor & Francis Group, LLC, Boca RatonGoogle Scholar
  6. Cao C, Arendash GW, Dickson A, Mamcarz MB, Lin X, Ethell DW (2009) Abeta-specific Th2 cells provide cognitive and pathological benefits to Alzheimer's mice without infiltrating the CNS. Neurobiol Dis 34(1):63–70. doi: 10.1016/j.nbd.2008.12.015 PubMedCrossRefGoogle Scholar
  7. Cao C, Lin X, Zhang C, Wahi M, Wefes I, Arendash G, Potter H (2008) Mutant amyloid-beta-sensitized dendritic cells as Alzheimer's disease vaccine. Journal of Neuroimmunology 200(1–2):1–10PubMedCrossRefGoogle Scholar
  8. Cohen S, Haimovich J, Hollander N (2005) B-cell lymphoma and myeloma protection induced by idiotype vaccination with dendritic cells is mediated entirely by T cells in mice. In: J Immunother, vol 28. vol 5. United States, pp 461–466Google Scholar
  9. Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B (2003) RAGE mediates amyloid-beta peptide transport across the blood–brain barrier and accumulation in brain. In: Nat Med, vol 9. vol 7. United States, pp 907–913. doi: 10.1038/nm890
  10. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM (2001) Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. In: Proc Natl Acad Sci U S A, vol 98. vol 15. United States, pp 8850–8855. doi: 10.1073/pnas.151261398
  11. Dodart JC, Meziane H, Mathis C, Bales KR, Paul SM, Ungerer A (1999) Behavioral disturbances in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Behav Neurosci 113(5):982–990PubMedCrossRefGoogle Scholar
  12. Chen et al (2000) A learning deficit related to age and beta-amyloid plaques in a mouse model of. Nature 408(6815):975–979CrossRefGoogle Scholar
  13. Gajewski TF, Fallarino F, Ashikari A, Sherman M (2001) Immunization of HLA-A2+ melanoma patients with MAGE-3 or MelanA peptide-pulsed autologous peripheral blood mononuclear cells plus recombinant human interleukin 12. Clin Cancer Res 7(3 Suppl):895s–901sPubMedGoogle Scholar
  14. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373(6514):523–527. doi: 10.1038/373523a0 PubMedCrossRefGoogle Scholar
  15. Götz J, Eckert A, Matamales M, Ittner L, Liu X (2011) Modes of Aβ toxicity in Alzheimer’s disease. Cellular and Molecular Life Sciences:1–17. doi: 10.1007/s00018-011-0750-2
  16. Hart DN (1997) Dendritic cells: unique leukocyte populations which control the primary immune response. Blood 90(9):3245–3287PubMedGoogle Scholar
  17. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392(6673):245–252PubMedCrossRefGoogle Scholar
  18. Karlnoski RA, Rosenthal A, Alamed J, Ronan V, Gordon MN, Gottschall PE, Grimm J, Pons J, Morgan D (2008) Deglycosylated anti-Abeta antibody dose–response effects on pathology and memory in APP transgenic mice. J Neuroimmune Pharmacol 3(3):187–197. doi: 10.1007/s11481-008-9114-6 PubMedCrossRefGoogle Scholar
  19. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. In: Science, vol 300. vol 5618. United States, pp 486–489. doi: 10.1038/nm1782, 10.1126/science.1079469
  20. Koldamova RP, Lefterov IM, Ikonomovic MD, Skoko J, Lefterov PI, Isanski BA, DeKosky ST, Lazo JS (2003) 22R-hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid beta secretion. J Biol Chem 278(15):13244–13256. doi: 10.1074/jbc.M300044200 PubMedCrossRefGoogle Scholar
  21. Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D, Koldamova R (2007) Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment. Mol Neurodegener 2:20PubMedCrossRefGoogle Scholar
  22. Loveland BE, Zhao A, White S, Gan H, Hamilton K, Xing PX, Pietersz GA, Apostolopoulos V, Vaughan H,Karanikas V, Kyriakou P, McKenzie IF, Mitchell PL (2006) Mannan-MUC1-pulsed dendritic cellimmunotherapy: a phase I trial in patients with adenocarcinoma. In: Clin Cancer Res, vol 12. vol 3 Pt 1. United States, pp 869–877. doi: 10.1158/1078-0432.ccr-05-1574
  23. Mathews PM, Nixon RA (2003) Setback for an Alzheimer's disease vaccine: lessons learned. Neurology 61(1):7–8PubMedCrossRefGoogle Scholar
  24. Merck (2007 - [cited] 2011 Aug 30) A study of V950 in people with Alzheimer Disease (V950-001). In: [Internet].
  25. Mittendorf EA, Storrer CE, Foley RJ, Harris K, Jama Y, Shriver CD, Ponniah S, Peoples GE (2006) Evaluation of the HER2/neu-derived peptide GP2 for use in a peptide-based breast cancer vaccine trial. Cancer 106(11):2309–2317. doi: 10.1002/cncr.21849 PubMedCrossRefGoogle Scholar
  26. Morgan D (2011) Immunotherapy for Alzheimer's disease. J Intern Med 269(1):54–63. doi: 10.1111/j.1365- 2796.2010.02315.x PubMedCrossRefGoogle Scholar
  27. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408(6815):982–985. doi: 10.1038/35050116 PubMedCrossRefGoogle Scholar
  28. Mosca PJ, Lyerly HK, Clay TM, Morse MA (2007) Dendritic cell vaccines. In: Front Biosci, vol 12. United States, pp 4050–4060Google Scholar
  29. NA A, JJ, D M (2010) Direct observation of the kinetic mechanisms for Aß peptide aggregation: Towards elucidating Alzheimer plaque dissolution. vol 6:S247. Alzheimers Dement.Google Scholar
  30. Novartus (2011) To Investigate the Safety and Tolerability of Repeated Subcutaneous Injections of CAD106 in Alzheimer's Patients. [Internet], Bethesda (MD): National Library of Medicine (US)Google Scholar
  31. Octave JN (1995) The amyloid peptide and its precursor in Alzheimer’s disease. Rev Neurosci 6(4):287–316PubMedCrossRefGoogle Scholar
  32. Panza F, Frisardi V, Imbimbo BP, Seripa D, Solfrizzi V, Pilotto A (2011) Monoclonal antibodies against beta-amyloid (Abeta) for the treatment of Alzheimer's disease: the Abeta target at a crossroads. Expert Opin Biol Ther 11(6):679–686. doi: 10.1517/14712598.2011.579099 PubMedCrossRefGoogle Scholar
  33. Pfizer, JANSSEN Alzheimer Immunotherapy Research & Development L (2007 - [cited] 2011 Aug 30) Study Evaluating ACC-001 In Subjects With Mild To Moderate Alzheimer's Disease. In: [Internet].
  34. Pillay NS, Kellaway LA, Kotwal GJ (2004) Molecular mechanisms, emerging etiological insights and models to test potential therapeutic interventions in Alzheimer’s disease. Curr Alzheimer Res 1(4):295–306PubMedCrossRefGoogle Scholar
  35. Postupna N, Rose SE, Bird TD, Gonzalez-Cuyar LF, Sonnen JA, Larson EB, Keene CD, Montine TJ (2011) Novel antibody capture assay for paraffin-embedded tissue detects wide-ranging amyloid beta and paired helical filament-tau accumulation in cognitively normal older adults. Brain Pathol. doi: 10.1111/j.1750-3639.2011.00542.x
  36. Reitz C, Brayne C, Mayeux R (2012) Epidemiology of Alzheimer disease.Google Scholar
  37. Satthaporn S, Eremin O (2001) Dendritic cells (II): Role and therapeutic implications in cancer. J R Coll Surg Edinb 46(3):159–167PubMedGoogle Scholar
  38. Saxena U (2011) Bioenergetics breakdown in Alzheimer's disease: targets for new therapies. Int J Physiol Pathophysiol Pharmacol 3(2):133–139PubMedGoogle Scholar
  39. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid- beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400(6740):173–177. doi: 10.1038/22124 PubMedCrossRefGoogle Scholar
  40. Scholtzova H, Kascsak RJ, Bates KA, Boutajangout A, Kerr DJ, Meeker HC, Mehta PD, Spinner DS, Wisniewski T (2009) Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology. In: J Neurosci, vol 29. vol 6. United States, pp 1846–1854. doi: 10.1523/jneurosci.5715-08.2009
  41. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14(8):837–842PubMedCrossRefGoogle Scholar
  42. Sigurdsson EM, Wisniewski T, Frangione B (2002) A safer vaccine for Alzheimer's disease? In: Neurobiol Aging, vol 23. vol 6. United States, pp 1001–1008Google Scholar
  43. Simons M, Keller P, Dichgans J, Schulz JB (2001) Cholesterol and Alzheimer's disease: is there a link? Neurology 57(6):1089–1093PubMedCrossRefGoogle Scholar
  44. Smit WM, Rijnbeek M, van Bergen CA, de Paus RA, Vervenne HA, van de Keur M, Willemze R, Falkenburg JH (1997) Generation of dendritic cells expressing bcr-abl from CD34-positive chronic myeloid leukemia precursor cells. In: Hum Immunol, vol 53. vol 2. United States, pp 216–223. doi: 10.1016/s0198-8859(96)00285-6
  45. Solomon B, Koppel R, Frankel D, Hanan-Aharon E (1997) Disaggregation of Alzheimer beta-amyloid by site- directed mAb. Proc Natl Acad Sci U S A 94(8):4109–4112PubMedCrossRefGoogle Scholar
  46. Stein VM, Baumgartner W, Schroder S, Zurbriggen A, Vandevelde M, Tipold A, Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, Landreth GE, Vinters HV, Tontonoz P (2007) Differential expression of CD45 on canine microglial cells attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. In: J Vet Med A Physiol Pathol Clin Med, vol 54. vol 6. Germany, United States, pp 314–320. doi: 10.1172/jci3190910.1111/j.1439-0442.2007.00926.x
  47. Steinman RM (2001) Dendritic cells and the control of immunity: enhancing the efficiency of antigen presentation. Mt Sinai J Med 68(3):160–166PubMedGoogle Scholar
  48. Tabira T (2010) Immunization therapy for Alzheimer disease: a comprehensive review of active immunization strategies. In: Tohoku J Exp Med, vol 220. vol 2. Japan, pp 95–106Google Scholar
  49. Tsai KJ, Tsai YC, Shen CK (2007) G-CSF rescues the memory impairment of animal models of Alzheimer's disease. In: J Exp Med, vol 204. vol 6. United States, pp 1273–1280. doi: 10.1084/jem.20062481
  50. Tuppo EE, Arias HR (2005) The role of inflammation in Alzheimer's disease. In: Int J Biochem Cell Biol, vol 37. vol 2. England, pp 289–305. doi: 10.1016/j.biocel.2004.07.009
  51. Van Norden AGW, van Dijk EJ, de Laat KF, Scheltens P, OldeRikkert MGM, de Leeuw FE, Vellas B, Black R, Thal LJ, Fox NC, Daniels M, McLennan G, Tompkins C, Leibman C, Pomfret M, Grundman M (2009) Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res 6(2):144–151CrossRefGoogle Scholar
  52. Zhu Y, Hou H, Rezai-Zadeh K, Giunta B, Ruscin A, Gemma C, Jin J, Dragicevic N, Bradshaw P, Rasool S, Glabe CG, Ehrhart J, Bickford P, Mori T, Obregon D, Town T, Tan J (2011) CD45 deficiency drives amyloid- beta peptide oligomers and neuronal loss in Alzheimer's disease mice. J Neurosci 31(4):1355–1365. doi: 10.1523/jneurosci.3268-10.2011 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Zhongqiu Luo
    • 1
  • Jialin Li
    • 2
    • 3
  • Neel R. Nabar
    • 4
    • 5
  • Xiaoyang Lin
    • 5
  • Ge Bai
    • 6
  • Jianfeng Cai
    • 6
  • Shu-Feng Zhou
    • 4
  • Chuanhai Cao
    • 4
    • 5
  • Jinhuan Wang
    • 3
  1. 1.Department of NeurosurgeryTianjin First Center HospitalTianjinChina
  2. 2.Tianjin Medical UniversityTianjinChina
  3. 3.Department of NeurosurgeryTianjin Huan Hu HospitalTianjinChina
  4. 4.Department of Pharmaceutical Sciences, College of PharmacyUniversity of South FloridaTampaUSA
  5. 5.USF-Health Byrd Alzheimer’s InstituteUniversity of South Florida HealthTampaUSA
  6. 6.Department of ChemistryUniversity of South FloridaTampaUSA

Personalised recommendations