Novel Abeta immunogens: is shorter better?
Active and passive Abeta immunotherapy in Alzheimer's disease (AD)-like mouse models lowers cerebral amyloid-beta protein (Abeta) levels, especially if given early in the disease process, and improves cognitive deficits. In 2002, a Phase IIa clinical trial was halted due to meningoencephalitis in approximately 6% of the AD patients. It is hypothesized that the immunogen, full-length Abeta1-42, may have led to an autoimmune response. Currently, we are developing novel Abeta peptide immunogens for active immunization in amyloid precursor protein transgenic mice (APP Tg) to target Abeta B cell epitopes (within Abeta1-15) and avoid Abeta-specific T cell epitopes (Abeta16-42) so as to generate a safe and effective AD vaccine. Intranasal immunization with dendrimeric Abeta1-15 (16 copies of Abeta1-15 on a lysine core) or a tandem repeat of Abeta1-15 joined by 2 lysines and conjugated to an RGD motif with a mutated form of an E. coli-derived adjuvant generated robust Abeta titers in both wildtype and APP Tg mice. The Abeta antibodies recognized a B cell epitope within Abeta1-7, were mostly T-helper 2 associated immunoglobulin isotypes, bound human AD and APP Tg plaques, and detected Abeta oligomers. Splenic T cells reacted to the immunogens but not full-length Abeta. Six months of intranasal immunization (from 6-to-12 months of age) of J20 mice with each immunogen lowered insoluble Abeta42 by 50%, reduced plaque burden and gliosis, and increased Abeta in plasma. Interestingly, Abeta antibody generation was influenced by route of immunization. Transcutaneous immunization with dbeta1-15, but not full-length Abeta, led to high Abeta titers. In summary, our short Abeta immunogens induced robust titers of predominantly Th2 antibodies that were able to clear cerebral Abeta in the absence of Abeta-specific T cell reactivity, indicating the potential for a safer vaccine. We remain optimistic about the potential of such a vaccine for prevention and treatment of AD.
Lemere
Cynthia A
CA
Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115 USA. clemere@rics.bwh.harvard.edu
Maier
Marcel
M
Peng
Ying
Y
Jiang
Liying
L
Seabrook
Timothy J
TJ
D000544:Alzheimer Disease / Q000276:immunology* / Q000517:prevention & control*; D023582:Alzheimer Vaccines / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use*
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments