Active and passive Aβ immunotherapy in Alzheimers disease (AD)-like mouse models lowers cerebral amyloid- β protein (Aβ) 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 ∼6% of the AD patients. It is hypothesized that the immunogen, full-length Aβ1-42, may have led to an autoimmune response. Currently, we are developing novel Aβ peptide immunogens for active immunization in amyloid precursor protein transgenic mice (APP Tg) to target Aβ B cell epitopes (within Aβ1-15) and avoid Aβ-specific T cell epitopes (Aβ16-42) so as to generate a safe and effective AD vaccine. Intranasal immunization with dendrimeric Aβ1-15 (16 copies of Aβ1-15 on a lysine core) or a tandem repeat of Aβ1-15 joined by 2 lysines and conjugated to an RGD motif with a mutated form of an E. coli-derived adjuvant generated robust Aβ titers in both wildtype and APP Tg mice. The Aβ antibodies recognized a B cell epitope within Aβ1-7, were mostly T-helper 2 associated immunoglobulin isotypes, bound human AD and APP Tg plaques, and detected Aβ oligomers. Splenic T cells reacted to the immunogens but not full-length Aβ. Six months of intranasal immunization (from 6-to-12 months of age) of J20 mice with each immunogen lowered insoluble Aβ42 by 50%, reduced plaque burden and gliosis, and increased Aβ in plasma. Interestingly, Aβ antibody generation was influenced by route of immunization. Transcutaneous immunization with dβ1-15, but not full-length Abeta, led to high Aβ titers. In summary, our short Aβ immunogens induced robust titers of predominantly Th2 antibodies that were able to clear cerebral Aβ in the absence of Aβ-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.
Aβ immunotherapy, Alzheimer's disease, vaccination, T cells, B cells
Center for Neurologic Diseases,NRB 636F, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.