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Doubly Phosphorylated Peptide Vaccines to Protect Transgenic P301S Mice against Alzheimer's Disease Like Tau Aggregation.

Richter M, Mewes A, Fritsch M, Krügel U, Hoffmann R, Singer D - Vaccines (Basel) (2014)

Bottom Line: The effectiveness of the immunization was surveyed by evaluating the animal behavior, as well as the pathology in the brain by biochemical and histochemical techniques.Additionally, they performed significantly better in rotarod and beam walk tests at the age of 20 weeks, indicating that the disease development was slowed down.In conclusion, the data provide strong evidence that active immune therapies can reduce toxic effects of deposits formed in AD.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Deutscher Platz 5, Leipzig 04103, Germany. monique_richter@gmx.de.

ABSTRACT
Intracellular neurofibrillary tangles and extracellular senile plaques are potential targets for active and passive immunotherapies. In this study we used the transgenic mouse model P301S for active immunizations with peptide vaccines composed of a double phosphorylated tau neoepitope (pSer202/pThr205, pThr212/pSer214, pThr231/pSer235) and an immunomodulatory T cell epitope from the tetanus toxin or tuberculosis antigen Ag85B. Importantly, the designed vaccine combining Alzheimer's disease (AD) specific B cell epitopes with foreign (bacterial) T cell epitopes induced fast immune responses with high IgG₁ titers after prophylactic immunization that subsequently decreased over the observation period. The effectiveness of the immunization was surveyed by evaluating the animal behavior, as well as the pathology in the brain by biochemical and histochemical techniques. Immunized mice clearly lived longer with reduced paralysis than placebo-treated mice. Additionally, they performed significantly better in rotarod and beam walk tests at the age of 20 weeks, indicating that the disease development was slowed down. Forty-eight weeks old vaccinated mice passed the beam walk test significantly better than control animals, which together with the increased survival rates undoubtedly prove the treatment effect. In conclusion, the data provide strong evidence that active immune therapies can reduce toxic effects of deposits formed in AD.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the peptide vaccine design combining AD specific doubly phosphorylated epitopes of the tau protein (B cell epitope) via a tetrapeptide to foreign T cell epitopes to stimulate a non-inflammatory immune response.
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vaccines-02-00601-f002: Schematic representation of the peptide vaccine design combining AD specific doubly phosphorylated epitopes of the tau protein (B cell epitope) via a tetrapeptide to foreign T cell epitopes to stimulate a non-inflammatory immune response.

Mentions: All six peptides (Figure 2, Table 1) were synthesized in two steps connecting any of the three studied tau sequences (B cell epitope) via the GPSL linker sequence to either of the two T cell epitopes [28,47] with purities of 85 to 95% according to the peak areas of the reversed phase chromatograms. The post-synthetic global phosphorylation of positions Ser202/Thr205, Thr212/Ser214, and Thr231/Ser235 was very efficient yielding dominantly the desired double phosphorylated tau peptide, contaminated only with small amounts of single (TBC-Tau199–208[pS202/pT205] and TT-Tau229–237[pT231/pS235]) or triple phosphorylated peptides (TBC-Tau199–208[pS202/pT205] and TT-Tau199–208[pS202/pT205]). The yields ranged from 9.8% to 22.8% (Table 2). Further information regarding the peptide design and a detailed evaluation of their immunological properties with respect to specificity and cross reactivity can be found elsewhere [28].


Doubly Phosphorylated Peptide Vaccines to Protect Transgenic P301S Mice against Alzheimer's Disease Like Tau Aggregation.

Richter M, Mewes A, Fritsch M, Krügel U, Hoffmann R, Singer D - Vaccines (Basel) (2014)

Schematic representation of the peptide vaccine design combining AD specific doubly phosphorylated epitopes of the tau protein (B cell epitope) via a tetrapeptide to foreign T cell epitopes to stimulate a non-inflammatory immune response.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494214&req=5

vaccines-02-00601-f002: Schematic representation of the peptide vaccine design combining AD specific doubly phosphorylated epitopes of the tau protein (B cell epitope) via a tetrapeptide to foreign T cell epitopes to stimulate a non-inflammatory immune response.
Mentions: All six peptides (Figure 2, Table 1) were synthesized in two steps connecting any of the three studied tau sequences (B cell epitope) via the GPSL linker sequence to either of the two T cell epitopes [28,47] with purities of 85 to 95% according to the peak areas of the reversed phase chromatograms. The post-synthetic global phosphorylation of positions Ser202/Thr205, Thr212/Ser214, and Thr231/Ser235 was very efficient yielding dominantly the desired double phosphorylated tau peptide, contaminated only with small amounts of single (TBC-Tau199–208[pS202/pT205] and TT-Tau229–237[pT231/pS235]) or triple phosphorylated peptides (TBC-Tau199–208[pS202/pT205] and TT-Tau199–208[pS202/pT205]). The yields ranged from 9.8% to 22.8% (Table 2). Further information regarding the peptide design and a detailed evaluation of their immunological properties with respect to specificity and cross reactivity can be found elsewhere [28].

Bottom Line: The effectiveness of the immunization was surveyed by evaluating the animal behavior, as well as the pathology in the brain by biochemical and histochemical techniques.Additionally, they performed significantly better in rotarod and beam walk tests at the age of 20 weeks, indicating that the disease development was slowed down.In conclusion, the data provide strong evidence that active immune therapies can reduce toxic effects of deposits formed in AD.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Deutscher Platz 5, Leipzig 04103, Germany. monique_richter@gmx.de.

ABSTRACT
Intracellular neurofibrillary tangles and extracellular senile plaques are potential targets for active and passive immunotherapies. In this study we used the transgenic mouse model P301S for active immunizations with peptide vaccines composed of a double phosphorylated tau neoepitope (pSer202/pThr205, pThr212/pSer214, pThr231/pSer235) and an immunomodulatory T cell epitope from the tetanus toxin or tuberculosis antigen Ag85B. Importantly, the designed vaccine combining Alzheimer's disease (AD) specific B cell epitopes with foreign (bacterial) T cell epitopes induced fast immune responses with high IgG₁ titers after prophylactic immunization that subsequently decreased over the observation period. The effectiveness of the immunization was surveyed by evaluating the animal behavior, as well as the pathology in the brain by biochemical and histochemical techniques. Immunized mice clearly lived longer with reduced paralysis than placebo-treated mice. Additionally, they performed significantly better in rotarod and beam walk tests at the age of 20 weeks, indicating that the disease development was slowed down. Forty-eight weeks old vaccinated mice passed the beam walk test significantly better than control animals, which together with the increased survival rates undoubtedly prove the treatment effect. In conclusion, the data provide strong evidence that active immune therapies can reduce toxic effects of deposits formed in AD.

No MeSH data available.


Related in: MedlinePlus