Novel Ap Immunogens: Is Shorter Better?

Active and passive A beta immunotherapy in Alzheimer's disease (AD)-like mouse models lowers cerebral amyloid-P protein (A beta) 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 similar to 6% of the AD patients. It is hypothesized that the immunogen, full-length A beta 1-42, may have led to an autoimmune response. Currently, we are developing novel A beta peptide immunogens for active immunization in amyloid precursor protein transgenic mice (APP Tg) to target A beta B cell epitopes. (within A beta 1-15) and avoid A beta-specific T cell epitopes (A beta 16-42) so as to generate a safe and effective A beta vaccine. Intranasal immunization with dendrimeric A beta t-15 (16 copies of A beta 1-15 on a lysine core) or a tandem repeat of A beta 1-15 joined by 2 lysines and conjugated to an RGD motif with a mutated form of an E. coli-derived adjuvant generated robust A beta titers in both wildtype and APP Tg mice. The A beta antibodies recognized a B cell epitope within A beta 1-7, were mostly T-helper 2 associated immunoglobulin isotypes, bound human AD and APP Tg plaques, and detected A beta oligomers. Splenic T cells reacted to the immunogens but not full-length A beta. Six months of intranasal immunization (from 6-to-12 months of age) of J20 mice with each immunogen lowered insoluble A beta 42 by 50%, reduced plaque burden and gliosis, and increased A beta in plasma. Interestingly, A beta antibody generation was influenced by route of immunization. Transcutaneous immunization with d beta l-15, but not full-length Abeta, led to high A beta titers. In summary, our short A beta immunogens induced robust titers of predominantly Th2 antibodies that were able to clear cerebral A beta in the absence of A beta-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.