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

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by overproduction of β-amyloid (Aβ), which is formed from amyloid precursor protein (APP), with the subsequent pathologic deposition of Aβ in regions of the brain important for memory and cognition. Recently, vaccination of murine models of AD that exhibit Aβ 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 Aβ 1-42 peptide protects these mice from the memory deficits they would ordinarily develop. This report further characterizes the Aβ 1-42 peptide vaccine in mice. Anti-Aβ response time course analysis indicated that at least three vaccinations (each 100 μg) were necessary to elicit a significant anti-Aβ titer. Subsequent vaccinations resulted in half-maximal antibody titers of at least 10,000, and these titers were maintained 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 Aβ peptide. Also, measurement of specific murine Ig isotypes in Aβ-vaccinated mice demonstrated a predominant IgG₁ and IgG_2b response, suggesting a type 2 (Th2) T-helper cell immune response, which drives humoral immunity. Finally, lymphocyte proliferation assay experiments using Aβ peptides and splenocytes from vaccinated mice demonstrated that the vaccine specifically stimulates T-cell epitopes present within the Aβ peptide.