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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

Performance of P301S mice treated with the placebo (black, n = 20), immunized with Tau199–208[pS202/pT205] (blue, n = 15), Tau209–217[pT212/pS214] (red, n = 16), or Tau229–237[pT231/pS235] (green, n = 20), and non-transgenic control mice (white, n = 19) in rotarod, wire hang and beam walk tests. Statistical significances are marked by asterisks (*, p < 0.05). Given is the age of the mice at which the behavioral test was carried out (we = weeks).
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vaccines-02-00601-f008: Performance of P301S mice treated with the placebo (black, n = 20), immunized with Tau199–208[pS202/pT205] (blue, n = 15), Tau209–217[pT212/pS214] (red, n = 16), or Tau229–237[pT231/pS235] (green, n = 20), and non-transgenic control mice (white, n = 19) in rotarod, wire hang and beam walk tests. Statistical significances are marked by asterisks (*, p < 0.05). Given is the age of the mice at which the behavioral test was carried out (we = weeks).

Mentions: Due to the significant increase of body weight, the performance of non-transgenic mice did not improve over a period of 28 weeks in accelerating rotarod and wire-hang test. At the beam walk test over this time period an improvement of the number of foot slips was observed. Transgenic mice vaccinated with Tau199–208[pS202/pT205] showed significantly better motor functions at weeks 20 and 32 in rotarod and beam walk tests than placebo-treated mice, e.g., the latency to fall at the rotarod was in average 123 second for Tau199–208[pS202/pT205] vaccinated and only 86 second for placebo-treated mice. Among all three tests, the beam walk revealed a significant better performance of vaccinated animals than compared to placebo-treated mice (Figure 8, right panel). The average number of foot slips at 48 weeks of age for the placebo-treated mice was 7 whereas only 2–5 foot slips were counted for vaccinated mice. Most importantly, this was statistically significant for vaccines Tau199–208[pS202/pT205] and Tau229–237[pT231/pS235] relative to the placebo group. It should be noted, that the beam walk test is the least challenging test applied here and thus is indicative of already slight improvements of motor capabilities.


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)

Performance of P301S mice treated with the placebo (black, n = 20), immunized with Tau199–208[pS202/pT205] (blue, n = 15), Tau209–217[pT212/pS214] (red, n = 16), or Tau229–237[pT231/pS235] (green, n = 20), and non-transgenic control mice (white, n = 19) in rotarod, wire hang and beam walk tests. Statistical significances are marked by asterisks (*, p < 0.05). Given is the age of the mice at which the behavioral test was carried out (we = weeks).
© Copyright Policy
Related In: Results  -  Collection

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

vaccines-02-00601-f008: Performance of P301S mice treated with the placebo (black, n = 20), immunized with Tau199–208[pS202/pT205] (blue, n = 15), Tau209–217[pT212/pS214] (red, n = 16), or Tau229–237[pT231/pS235] (green, n = 20), and non-transgenic control mice (white, n = 19) in rotarod, wire hang and beam walk tests. Statistical significances are marked by asterisks (*, p < 0.05). Given is the age of the mice at which the behavioral test was carried out (we = weeks).
Mentions: Due to the significant increase of body weight, the performance of non-transgenic mice did not improve over a period of 28 weeks in accelerating rotarod and wire-hang test. At the beam walk test over this time period an improvement of the number of foot slips was observed. Transgenic mice vaccinated with Tau199–208[pS202/pT205] showed significantly better motor functions at weeks 20 and 32 in rotarod and beam walk tests than placebo-treated mice, e.g., the latency to fall at the rotarod was in average 123 second for Tau199–208[pS202/pT205] vaccinated and only 86 second for placebo-treated mice. Among all three tests, the beam walk revealed a significant better performance of vaccinated animals than compared to placebo-treated mice (Figure 8, right panel). The average number of foot slips at 48 weeks of age for the placebo-treated mice was 7 whereas only 2–5 foot slips were counted for vaccinated mice. Most importantly, this was statistically significant for vaccines Tau199–208[pS202/pT205] and Tau229–237[pT231/pS235] relative to the placebo group. It should be noted, that the beam walk test is the least challenging test applied here and thus is indicative of already slight improvements of motor capabilities.

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