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Mixed Effects Of Active Immunization Against Aß In An Alzheimer Mouse Model
Author(s) -
Oberman Klaske,
Hoogerhout Peter,
Gouweleeuw Leonie,
Eisel Ulrich L.M.,
van Riet Elly,
Schoemaker Regien G.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.05087
Subject(s) - tetanus , morris water navigation task , toxoid , immunization , phenotype , alzheimer's disease , medicine , immunology , vaccination , cognition , biology , disease , neuroscience , antibody , biochemistry , gene
Since Aß plaques and cognitive function are often not related in Alzheimers disease (AD), attention has shifted towards the neurotoxic soluble oligomeric Aß as the culprit in AD. Accordingly, INTRAVAC developed a concept vaccine that is specifically directed towards these misfolded Aß molecules. A previous study indicated protection against Aß‐induced neuronal damage in vaccinated mice. The aim of this study is to investigate the effects of the vaccine in a mouse model for AD. Methods As model for AD, J20 mice, overexpressing the human Amyloid Precursor Protein were used. AD phenotype of J20 mice was evaluated at 6 months of age. The vaccine consisted of 3 cyclic Aß peptides, conjugated to tetanus toxoid with proper adjuvants. Mock control consisted of tetanus toxoid +adjuvants. Mice were vaccinated or mock treated at 2,3 and 4 months of age, while behavior and plaque formation were evaluated at 6, 9 and 12 months of age. Results AD phenotype of J20 mice was confirmed by significant decline in cognitive performance, as well as the presence of plaques. Vaccinated mice showed significant improvement of working memory at 12 months compared to mock, as tested as correct alternations in Y‐maze exploration; 59.2±1.3 vs 56.1±1.6%. However, spatial learning (AUC learning curve: 858±±29 vs758±43s) and memory (number of platform crossings: 0.47±0.19 vs 1.04±0.39), measured in the Morris Water Maze, appeared deteriorated at 12 months. Plaque load, measured as number times size, increased with age, but was even slightly higher in vaccinated compared to mock mice at 12 months;9356±1200 vs 8155±1142 pixels). Antibody response showed significant titers for the cyclic peptides, but insignificant levels for Aß. Conclusion Cognitive decline and plaque formation in 6 months old J20 mice provide a relevant model for AD to test effects of vaccination against oligomeric Aß. Although vaccination at young ages improved working memory at 12 months, spatial learning and memory rather deteriorated, and plaque formation was not reduced. The lack of antibody response to Aß suggests that behavioral effects are mediated by mechanisms other than Aß reduction. Support or Funding Information Studies are partly funded by INTRAVACC, the Netherlands