QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, May 3, 2006, 26(18):4717-4728; doi:10.1523/JNEUROSCI.0381-06.2006

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (42) Citing Articles via Google Scholar Google Scholar Articles by Maier, M. Articles by Lemere, C. A. Search for Related Content PubMed PubMed Citation Articles by Maier, M. Articles by Lemere, C. A. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Alzheimer's Disease Learning Disorders

 Previous Article  |  Next Article 

Neurobiology of Disease
Short Amyloid- (A) Immunogens Reduce Cerebral A Load and Learning Deficits in an Alzheimer's Disease Mouse Model in the Absence of an A-Specific Cellular Immune Response

Marcel Maier,¹ Timothy J. Seabrook,¹ Noel D. Lazo,² Liying Jiang,¹ Pritam Das,³ Christopher Janus,³ and Cynthia A. Lemere¹

¹Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, ²Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California 90095, and ³Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida 32224

Correspondence should be addressed to Dr. Cynthia A. Lemere, Center for Neurological Diseases, Harvard New Research Building, Room 636F, 77 Avenue Louis Pasteur, Boston, MA 02115. Email: clemere{at}rics.bwh.harvard.edu

Amyloid- (A) immunotherapy lowers cerebral A and improves cognition in mouse models of Alzheimer's disease (AD). A clinical trial using active immunization with A1–42 was suspended after 6% of patients developed meningoencephalitis, possibly because of a T-cell reaction against A. Nevertheless, beneficial effects were reported in antibody responders. Consequently, alternatives are required for a safer vaccine. The A1–15 sequence contains the antibody epitope(s) but lacks the T-cell reactive sites of full-length A1–42. Therefore, we tested four alternative peptide immunogens encompassing either a tandem repeat of two lysine-linked A1–15 sequences (2xA1–15) or the A1–15 sequence synthesized to a cross-species active T1 T-helper-cell epitope (T1-A1–15) and each with the addition of a three-amino-acid RGD (Arg-Gly-Asp) motif (R-2xA1–15; T1-R-A1–15). High anti-A antibody titers were observed in wild-type mice after intranasal immunization with R-2xA1–15 or 2xA1–15 plus mutant Escherichia coli heat-labile enterotoxin LT(R192G) adjuvant. Moderate antibody levels were induced after immunization with T1-R-A1–15 or T1-A1–15 plus LT(R192G). Restimulation of splenocytes with the corresponding immunogens resulted in moderate proliferative responses, whereas proliferation was absent after restimulation with full-length A or A1–15. Immunization of human amyloid precursor protein, familial AD (hAPP_FAD) mice with R-2xA1–15 or 2xA1–15 resulted in high anti-A titers of noninflammatory T-helper 2 isotypes (IgG1 and IgG2b), a lack of splenocyte proliferation against full-length A, significantly reduced A plaque load, and lower cerebral A levels. In addition, 2xA1–15-immunized hAPP_FAD animals showed improved acquisition of memory compared with vehicle controls in a reference-memory Morris water-maze behavior test that approximately correlated with anti-A titers. Thus, our novel immunogens show promise for future AD vaccines.

Key words: Alzheimer's disease; amyloid beta; A peptide; immunotherapy; behavior; T-cell; intranasal

---

Received Jan. 26, 2006; revised March 9, 2006; accepted March 20, 2006.

Correspondence should be addressed to Dr. Cynthia A. Lemere, Center for Neurological Diseases, Harvard New Research Building, Room 636F, 77 Avenue Louis Pasteur, Boston, MA 02115. Email: clemere{at}rics.bwh.harvard.edu

This article has been cited by other articles:

				D. Lambracht-Washington, B.-X. Qu, M. Fu, T. N. Eagar, O. Stuve, and R. N. Rosenberg DNA {beta}-Amyloid1-42 Trimer Immunization for Alzheimer Disease in a Wild-Type Mouse Model JAMA, October 28, 2009; 302(16): 1796 - 1802. [Abstract] [Full Text] [PDF]

				P. Bach, J.-A. Tschape, F. Kopietz, G. Braun, J. K. Baade, K.-H. Wiederhold, M. Staufenbiel, M. Prinz, T. Deller, U. Kalinke, et al. Vaccination with A{beta}-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral A{beta} and Lowers Plaque Burden in APP Transgenic Mice J. Immunol., June 15, 2009; 182(12): 7613 - 7624. [Abstract] [Full Text] [PDF]

				M. Maier, Y. Peng, L. Jiang, T. J. Seabrook, M. C. Carroll, and C. A. Lemere 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., June 18, 2008; 28(25): 6333 - 6341. [Abstract] [Full Text] [PDF]

				W. Farris, S. G. Schutz, J. R. Cirrito, G. M. Shankar, X. Sun, A. George, M. A. Leissring, D. M. Walsh, W. Q. Qiu, D. M. Holtzman, et al. Loss of Neprilysin Function Promotes Amyloid Plaque Formation and Causes Cerebral Amyloid Angiopathy Am. J. Pathol., July 1, 2007; 171(1): 241 - 251. [Abstract] [Full Text] [PDF]

				A. Muhs, D. T. Hickman, M. Pihlgren, N. Chuard, V. Giriens, C. Meerschman, I. van der Auwera, F. van Leuven, M. Sugawara, M.-C. Weingertner, et al. Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice PNAS, June 5, 2007; 104(23): 9810 - 9815. [Abstract] [Full Text] [PDF]

				C.-Y. Lin, T. Gurlo, R. Kayed, A. E. Butler, L. Haataja, C. G. Glabe, and P. C. Butler Toxic Human Islet Amyloid Polypeptide (h-IAPP) Oligomers Are Intracellular, and Vaccination to Induce Anti-Toxic Oligomer Antibodies Does Not Prevent h-IAPP-Induced {beta}-Cell Apoptosis in h-IAPP Transgenic Mice Diabetes, May 1, 2007; 56(5): 1324 - 1332. [Abstract] [Full Text] [PDF]

				N. Moretto, A. Bolchi, C. Rivetti, B. P. Imbimbo, G. Villetti, V. Pietrini, L. Polonelli, S. Del Signore, K. M. Smith, R. J. Ferrante, et al. Conformation-sensitive Antibodies against Alzheimer Amyloid-beta by Immunization with a Thioredoxin-constrained B-cell Epitope Peptide J. Biol. Chem., April 13, 2007; 282(15): 11436 - 11445. [Abstract] [Full Text] [PDF]

				S. T. DeKosky, E. E. Abrahamson, J. R. Ciallella, W. R. Paljug, S. R. Wisniewski, R. S. B. Clark, and M. D. Ikonomovic Association of Increased Cortical Soluble Abeta42 Levels With Diffuse Plaques After Severe Brain Injury in Humans Arch Neurol, April 1, 2007; 64(4): 541 - 544. [Abstract] [Full Text] [PDF]

				G. Chen, K. S. Chen, D. Kobayashi, R. Barbour, R. Motter, D. Games, S. J. Martin, and R. G. M. Morris Active {beta}-Amyloid Immunization Restores Spatial Learning in PDAPP Mice Displaying Very Low Levels of {beta}-Amyloid J. Neurosci., March 7, 2007; 27(10): 2654 - 2662. [Abstract] [Full Text] [PDF]

				W. V. Nikolic, Y. Bai, D. Obregon, H. Hou, T. Mori, J. Zeng, J. Ehrhart, R. D. Shytle, B. Giunta, D. Morgan, et al. Transcutaneous beta-amyloid immunization reduces cerebral beta-amyloid deposits without T cell infiltration and microhemorrhage PNAS, February 13, 2007; 104(7): 2507 - 2512. [Abstract] [Full Text] [PDF]

				E. D. Roberson and L. Mucke 100 Years and Counting: Prospects for Defeating Alzheimer's Disease Science, November 3, 2006; 314(5800): 781 - 784. [Abstract] [Full Text] [PDF]

				M. S. Buckwalter, B. S. Coleman, M. Buttini, R. Barbour, D. Schenk, D. Games, P. Seubert, and T. Wyss-Coray Increased T Cell Recruitment to the CNS after Amyloid beta1-42 Immunization in Alzheimer's Mice Overproducing Transforming Growth Factor-beta1. J. Neurosci., November 1, 2006; 26(44): 11437 - 11441. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help