P4‐314: Epitope‐specific amyloid‐β oligomer vaccination ameliorates amygdala‐dependent memory deficits and inhibits region‐to‐region spread of plaque pathology in APP/PS1 mice

We have previously identified an amyloid-β oligomer-selective epitope, namely cyclized-Serine-Asparagine-Lysine (cSNK), which is not present on Aβ fibrils or monomers. Antibodies against cSNK recognize authentic Aβ oligomers (AβOs) present in brain and CSF of human Alzheimer's disease (AD) patients and brain tissues of transgenic mouse models of AD, but not monomers or fibrils. Here, we conducted testing of cSNK as a vaccine in APP/PS1 mice. Sex matched cohorts of 38 APP/PS1 mice on a C3H/BL6 background were vaccinated subcutaneously with 100 μg of cSNK-KLH, with Emulsigen-D as adjuvant or Emulsigen-D alone, beginning at 3 months of age (MOA). Animals were treated monthly. Plasma was collected at baseline and throughout immunization. At 11 MOA, animals were tested for memory function with cued and contextual fear conditioning (CFC) tasks and the novel object recognition (NOR) task. Following sacrifice at 12 MOA, plaque load was determined with ThioflavinS. Plasma anti-cSNK titers were quantified using MagPlex immunoassay. The Shapiro-Wilk test determined data normality. Differences between groups and genders were tested using a regression model with categorical covariates (ANOVA) and t-test or Mann-Whitney test when appropriate, using XLSTAT V2014.6.04. Baseline and control (adjuvant-alone) anti-cSNK titers were below detection limits throughout the study. In comparison, anti-cSNK titers were elevated following immunization and remained at or above this benchmark throughout the study in cSNK-KLH treated animals. Vaccination with cSNK significantly improved performance in the Cued FC task, which tests amygdala-dependent memory. In contrast, performance was not significantly improved in the Contextual FC or NOR tasks, both indicative of hippocampus-dependent memory. Correspondingly, analysis of these regions show cSNK immunization had no effect on hippocampal plaque burden, but significant reductions in plaque burden were observed in the amygdala and parahippocampal cortex, both of which receive projections from the hippocampus. This study establishes that vaccination of APP/PS1 mice with cSNK generates a polyclonal response, and can ameliorate behavioural deterioration and propagation of amyloid pathology along pre-existing neural networks. Our data are consistent with the APP/PS1 hippocampus being a “generator” of AβO seeds, which are transmitted through efferent and afferent axonal fiber tracts.

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