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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

Specific total IgG titers of P301S mice immunized with Tau199–208[pS202/pT205] (blue triangle , n = 39), Tau209-217[pT212/pS214] (red circle , n = 39) or Tau229–237[pT231/pS235] (green square , n = 36). Animals were immunized and boosted twice, two and six weeks after. Sera were collected one week before (background) and again 1, 3, 7, 11, 15, 19, 23, 31, and 39 weeks after the first vaccination (day 0). Solid lines represent the IgG titers of vaccinated mice; dashed lines represent the unspecific immune response against the three antigens, which was detected in sera of placebo treated mice (n = 36). Shown are geometric means of IgG titers with the standard error of the mean (SEM).
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vaccines-02-00601-f003: Specific total IgG titers of P301S mice immunized with Tau199–208[pS202/pT205] (blue triangle , n = 39), Tau209-217[pT212/pS214] (red circle , n = 39) or Tau229–237[pT231/pS235] (green square , n = 36). Animals were immunized and boosted twice, two and six weeks after. Sera were collected one week before (background) and again 1, 3, 7, 11, 15, 19, 23, 31, and 39 weeks after the first vaccination (day 0). Solid lines represent the IgG titers of vaccinated mice; dashed lines represent the unspecific immune response against the three antigens, which was detected in sera of placebo treated mice (n = 36). Shown are geometric means of IgG titers with the standard error of the mean (SEM).

Mentions: All three doubly phosphorylated tau sequences induced strong and fast immune responses in 62.5% (Tau199–208[pS202/pT205]), 77.8% (Tau209–217[pT212/pS214]) and 100% (Tau229–237[pT231/pS235]) of P301S mice, reaching similar specific total IgG titers of approximately 50,000 after two injections within three weeks (Figure 3, Table S1, Table S2, Table S3). The specific total IgG titers did not further increase after the second boost, but remained stable until week 20 without any further vaccination. In the following months, the titer dropped slowly to approximately 2500. Cross-reactivities towards the T cell epitopes and non-immunized phospho-tau epitopes were below 1000 (data not shown).


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)

Specific total IgG titers of P301S mice immunized with Tau199–208[pS202/pT205] (blue triangle , n = 39), Tau209-217[pT212/pS214] (red circle , n = 39) or Tau229–237[pT231/pS235] (green square , n = 36). Animals were immunized and boosted twice, two and six weeks after. Sera were collected one week before (background) and again 1, 3, 7, 11, 15, 19, 23, 31, and 39 weeks after the first vaccination (day 0). Solid lines represent the IgG titers of vaccinated mice; dashed lines represent the unspecific immune response against the three antigens, which was detected in sera of placebo treated mice (n = 36). Shown are geometric means of IgG titers with the standard error of the mean (SEM).
© Copyright Policy
Related In: Results  -  Collection

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

vaccines-02-00601-f003: Specific total IgG titers of P301S mice immunized with Tau199–208[pS202/pT205] (blue triangle , n = 39), Tau209-217[pT212/pS214] (red circle , n = 39) or Tau229–237[pT231/pS235] (green square , n = 36). Animals were immunized and boosted twice, two and six weeks after. Sera were collected one week before (background) and again 1, 3, 7, 11, 15, 19, 23, 31, and 39 weeks after the first vaccination (day 0). Solid lines represent the IgG titers of vaccinated mice; dashed lines represent the unspecific immune response against the three antigens, which was detected in sera of placebo treated mice (n = 36). Shown are geometric means of IgG titers with the standard error of the mean (SEM).
Mentions: All three doubly phosphorylated tau sequences induced strong and fast immune responses in 62.5% (Tau199–208[pS202/pT205]), 77.8% (Tau209–217[pT212/pS214]) and 100% (Tau229–237[pT231/pS235]) of P301S mice, reaching similar specific total IgG titers of approximately 50,000 after two injections within three weeks (Figure 3, Table S1, Table S2, Table S3). The specific total IgG titers did not further increase after the second boost, but remained stable until week 20 without any further vaccination. In the following months, the titer dropped slowly to approximately 2500. Cross-reactivities towards the T cell epitopes and non-immunized phospho-tau epitopes were below 1000 (data not shown).

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