Background: While evidence accumulates for a role of epigenetic modifications in the
pathophysiological cascade of Alzheimer’s disease (AD), amyloid-β (Aβ)-targeted active immunotherapy
approaches are under investigation to prevent or slow the progression of AD. The impact of Aβ active
vaccines on epigenetic markers has not been studied thus far.
Objective: The current study aims to establish the relationship between active immunotherapy with a
MER5101-based vaccine (consisting of Aβ1-15 copies conjugated with a 7 aa spacer to the diphtheria
toxoid carrier protein, formulated in a Th2-biased adjuvant) and epigenetic DNA modifications in the
hippocampus of APPswe/PS1dE9 mice.
Methods: As we previously reported, immunotherapy started when the mice were 10 months of age and
behavioral testing occurred at 14 months of age, after which the mice were sacrificed for further analysis
of their brains. In this add-on study, global levels of DNA methylation and hydroxymethylation, and
DNA methyltransferase 3A (DNMT3A) were determined using quantitative immunohistochemistry, and
compared to our previously analyzed immunization-induced changes in AD-related neuropathology and
Results: Active immunization did not affect global DNA methylation levels but instead, resulted in decreased
DNA hydroxymethylation and DNMT3A levels. Independent of immunization, inverse correlations
with behavioral performance were observed for levels of DNA methylation and hydroxymethylation,
as well as DNMT3A, while Aβ pathology and synaptic markers did not correlate with DNA methylation
levels but did positively correlate with DNA hydroxymethylation and levels of DNMT3A.
Conclusion: Our results indicate that active Aβ vaccination has significant effects on the epigenome in
the hippocampus of APPswe/PS1dE9 mice, and suggest that DNA methylation and hydroxymethylation
may be involved in cognitive functioning.