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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

Quantitative immunohistochemistry of tau pathology in 48 weeks old P301S mice. Cells positively stained with mAbs AT8 and AT100 were counted within the pyramidal cell layer of region CA1 (left), CA2/3/4 (middle) and the granular cell layer of DG (right) of P301S mice treated with placebo (n = 7, ♦), Tau199–208[pS202/pT205] (n = 6, ), Tau209–217[pT212/pS214] (n = 9, ), or Tau229–237[pT231/pS235] (n = 9, ).
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vaccines-02-00601-f006: Quantitative immunohistochemistry of tau pathology in 48 weeks old P301S mice. Cells positively stained with mAbs AT8 and AT100 were counted within the pyramidal cell layer of region CA1 (left), CA2/3/4 (middle) and the granular cell layer of DG (right) of P301S mice treated with placebo (n = 7, ♦), Tau199–208[pS202/pT205] (n = 6, ), Tau209–217[pT212/pS214] (n = 9, ), or Tau229–237[pT231/pS235] (n = 9, ).

Mentions: At coronal brain slices of non-transgenic mice no immunostaining of phosphorylation dependent mAbs AT8 (Tau[pS202/pT205]) and AT100 (Tau[pT212/pS214]) could be found corroborating the lack of pathology in these mice (data not shown). In placebo-treated and vaccinated P301S mice both mAbs AT8 and AT100 stained neurons, which could be quantified (Figure 6). At 48 weeks the phospho-tau pathology was most obvious in the cortex, hippocampus, amygdala, piriform cortex, and hypothalamic region. The microscope images displayed star shaped structures comprised of a dense staining of the entire cell body and protrusions without staining of the nucleus (Figure S1, left). Within the hippocampal formation phospho-tau positive neurons appeared uniformly distributed in the visual field (Figure S1, right). The intensity of these structures increased from 32-week to 48-week-old 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)

Quantitative immunohistochemistry of tau pathology in 48 weeks old P301S mice. Cells positively stained with mAbs AT8 and AT100 were counted within the pyramidal cell layer of region CA1 (left), CA2/3/4 (middle) and the granular cell layer of DG (right) of P301S mice treated with placebo (n = 7, ♦), Tau199–208[pS202/pT205] (n = 6, ), Tau209–217[pT212/pS214] (n = 9, ), or Tau229–237[pT231/pS235] (n = 9, ).
© Copyright Policy
Related In: Results  -  Collection

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

vaccines-02-00601-f006: Quantitative immunohistochemistry of tau pathology in 48 weeks old P301S mice. Cells positively stained with mAbs AT8 and AT100 were counted within the pyramidal cell layer of region CA1 (left), CA2/3/4 (middle) and the granular cell layer of DG (right) of P301S mice treated with placebo (n = 7, ♦), Tau199–208[pS202/pT205] (n = 6, ), Tau209–217[pT212/pS214] (n = 9, ), or Tau229–237[pT231/pS235] (n = 9, ).
Mentions: At coronal brain slices of non-transgenic mice no immunostaining of phosphorylation dependent mAbs AT8 (Tau[pS202/pT205]) and AT100 (Tau[pT212/pS214]) could be found corroborating the lack of pathology in these mice (data not shown). In placebo-treated and vaccinated P301S mice both mAbs AT8 and AT100 stained neurons, which could be quantified (Figure 6). At 48 weeks the phospho-tau pathology was most obvious in the cortex, hippocampus, amygdala, piriform cortex, and hypothalamic region. The microscope images displayed star shaped structures comprised of a dense staining of the entire cell body and protrusions without staining of the nucleus (Figure S1, left). Within the hippocampal formation phospho-tau positive neurons appeared uniformly distributed in the visual field (Figure S1, right). The intensity of these structures increased from 32-week to 48-week-old 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