Limits...
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 titers of IgG1 (circles), IgG2a (squares), IgG2b (triangles) and IgG2c (crosses) in sera samples collected one week after the second boost from P301S mice immunized with Tau199–208[pS202/pT205] (n = 12, (A)), Tau209–217[pT212/pS214] (n = 12, (C)), Tau229–237[pT231/pS235] (n = 12, (E)). Subsequent time course of IgG subtype titers at different time points until the end of the immunization study (B,D,F). Statistical significance is indicated by asterisks (*, p < 0.05; **, p < 0.01; ***, p < 0.001).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4494214&req=5

vaccines-02-00601-f004: Specific titers of IgG1 (circles), IgG2a (squares), IgG2b (triangles) and IgG2c (crosses) in sera samples collected one week after the second boost from P301S mice immunized with Tau199–208[pS202/pT205] (n = 12, (A)), Tau209–217[pT212/pS214] (n = 12, (C)), Tau229–237[pT231/pS235] (n = 12, (E)). Subsequent time course of IgG subtype titers at different time points until the end of the immunization study (B,D,F). Statistical significance is indicated by asterisks (*, p < 0.05; **, p < 0.01; ***, p < 0.001).

Mentions: Detailed subtyping of a randomly chosen subset of 12 animals of each immunization group after the second boost (12- to 17-weeks-old P301S mice), showed IgG1 mean titers of 46,000 for Tau199–208[pS202/pT205], 38,500 for Tau209–217[pT212/pS214] and 55,000 for Tau229–237[pT231/pS235] (Figure 4, left column, Table S4, S5 and S6). Six of the 12 mice immunized with Tau199–208[pS202/pT205] and five of the 12 mice immunized with Tau209–217[pT212/pS214] and Tau229–237[pT231/pS235] showed no IgG2a titers at all, whereas the other 50% showed IgG2a, IgG2b, and IgG2c titers of approximately 1500 for mice immunized with Tau199–208[pS202/pT205] and Tau209–217[pT212/pS214]. Immunization with Tau229–237[pT231/pS235] initiated IgG2a titers below 500. IgG2b and IgG2c titers were detected in all sera of about 11,000. During the following month IgG1, IgG2a, IgG2b and IgG2c mean titers decreased continuously (Figure 4, right column) similar to the total specific IgG titers (Figure 3). It should be noted although IgG2a and IgG2c originate from the same IgG locus; both were analyzed because of the mixed BL6/C3H genetic background of the animals.


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 titers of IgG1 (circles), IgG2a (squares), IgG2b (triangles) and IgG2c (crosses) in sera samples collected one week after the second boost from P301S mice immunized with Tau199–208[pS202/pT205] (n = 12, (A)), Tau209–217[pT212/pS214] (n = 12, (C)), Tau229–237[pT231/pS235] (n = 12, (E)). Subsequent time course of IgG subtype titers at different time points until the end of the immunization study (B,D,F). Statistical significance is indicated by asterisks (*, p < 0.05; **, p < 0.01; ***, p < 0.001).
© Copyright Policy
Related In: Results  -  Collection

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

vaccines-02-00601-f004: Specific titers of IgG1 (circles), IgG2a (squares), IgG2b (triangles) and IgG2c (crosses) in sera samples collected one week after the second boost from P301S mice immunized with Tau199–208[pS202/pT205] (n = 12, (A)), Tau209–217[pT212/pS214] (n = 12, (C)), Tau229–237[pT231/pS235] (n = 12, (E)). Subsequent time course of IgG subtype titers at different time points until the end of the immunization study (B,D,F). Statistical significance is indicated by asterisks (*, p < 0.05; **, p < 0.01; ***, p < 0.001).
Mentions: Detailed subtyping of a randomly chosen subset of 12 animals of each immunization group after the second boost (12- to 17-weeks-old P301S mice), showed IgG1 mean titers of 46,000 for Tau199–208[pS202/pT205], 38,500 for Tau209–217[pT212/pS214] and 55,000 for Tau229–237[pT231/pS235] (Figure 4, left column, Table S4, S5 and S6). Six of the 12 mice immunized with Tau199–208[pS202/pT205] and five of the 12 mice immunized with Tau209–217[pT212/pS214] and Tau229–237[pT231/pS235] showed no IgG2a titers at all, whereas the other 50% showed IgG2a, IgG2b, and IgG2c titers of approximately 1500 for mice immunized with Tau199–208[pS202/pT205] and Tau209–217[pT212/pS214]. Immunization with Tau229–237[pT231/pS235] initiated IgG2a titers below 500. IgG2b and IgG2c titers were detected in all sera of about 11,000. During the following month IgG1, IgG2a, IgG2b and IgG2c mean titers decreased continuously (Figure 4, right column) similar to the total specific IgG titers (Figure 3). It should be noted although IgG2a and IgG2c originate from the same IgG locus; both were analyzed because of the mixed BL6/C3H genetic background of the animals.

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