Duration and Specificity of Humoral Immune Responses in Mice Vaccinated with the Alzheimer’s Disease-Associated b-Amyloid 1-42 Peptide

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by overproduction of b-amyloid (Ab), which is formed from amyloid precursor protein (APP), with the subsequent pathologic deposition of Ab in regions of the brain important for memory and cognition. Recently, vaccination of murine models of AD that exhibit Ab deposition has halted or delayed the usual progression of the pathology of AD. Our group has demonstrated that vaccination of a doubly transgenic mouse model (expressing mutant APP and presenilin-1) with the Ab1-42 peptide protects these mice from the memory deficits they would ordinarily develop. This report further characterizes the Ab1-42 peptide vaccine in mice. Anti-Ab response time course analysis in-dicated that at least three vaccinations (each 100 mg) were necessary to elicit a significant anti-Ab titer. Sub-sequent vaccinations resulted in half-maximal antibody titers of at least 10,000, and these titers were main-tained for at least 5 months after the final boost. Peptide binding competition studies indicated that the highest humoral responses are generated against the N terminus of the Ab peptide. Also, measurement of specific murine Ig isotypes in Ab-vaccinated mice demonstrated a predominant IgG1 and IgG2b response, suggesting a type 2 (Th2) T-helper cell immune response, which drives humoral immunity. Finally, lymphocyte prolif-eration assay experiments using Ab peptides and splenocytes from vaccinated mice demonstrated that the vaccine specifically stimulates T-cell epitopes present within the Ab peptide. 72