Intranasal immunotherapy for the treatment of Alzheimer’s disease: Escherichia coli LT and LT(R192G) as mucosal adjuvants

Alzheimer’s disease (AD) is the most common form of dementia worldwide, yet there is currently no effective treatment or cure. Extracellular deposition of amyloid-β protein (Aβ) in brain is a key neuropathological characteristic of AD. In 1999, Schenk et al. first reported that an injected Aβ vaccine given to PDAPP mice, an AD mouse model displaying Aβ deposition in brain, led to the lowering of Aβ levels in brain. In 2000, we demonstrated that intranasal (i.n.) immunization with human synthetic Aβ1–40 peptide for 7 months led to a 50–60% reduction in cerebral Aβ burden in PDAPP mice; serum Aβ antibody titers were low (not, vert, similar26 μg/ml). More recently, we have optimized our i.n. Aβ immunization protocol in wild-type (WT) mice. When low doses Escherichia coli heat-labile enterotoxin (LT) were given as a mucosal adjuvant with Aβ i.n., there was a dramatic 12-fold increase in Aβ antibody titers in WT B6D2F1 mice treated two times per week for 8 weeks compared to those of mice receiving i.n. Aβ without adjuvant. A non-toxic form of LT, designated LT(R192G), showed even better adjuvanticity; anti-Aβ antibody titers were 16-fold higher than those seen in mice given i.n. Aβ without adjuvant. In both cases, the serum Aβ antibodies recognized epitopes within Aβ1–15 and were of the immunoglobulin (Ig) isotypes IgG2b, IgG1, IgG2a and low levels of IgA. This new and improved Aβ vaccine protocol is now being tested in AD mouse models with the expectation that higher Aβ antibody titers may be more effective in reducing cerebral Aβ levels.