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Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy.

Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud PB, Head E, Biragyn A, Cribbs DH, Agadjanyan MG - PLoS ONE (2008)

Bottom Line: The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Abeta antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response.Importantly, vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages.Data from this transitional pre-clinical study suggest that our DNA epitope vaccine could be used as a safe and effective strategy for AD therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, California, United States of America.

ABSTRACT

Background: The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Abeta antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response. To achieve this goal we have designed a prototype chemokine-based DNA epitope vaccine expressing a fusion protein that consists of 3 copies of the self-B cell epitope of Abeta(42) (Abeta(1-11)) , a non-self T helper cell epitope (PADRE), and macrophage-derived chemokine (MDC/CCL22) as a molecular adjuvant to promote a strong anti-inflammatory Th2 phenotype.

Methods and findings: We generated pMDC-3Abeta(1-11)-PADRE construct and immunized 3xTg-AD mouse model starting at age of 3-4 months old. We demonstrated that prophylactic immunizations with the DNA epitope vaccine generated a robust Th2 immune response that induced high titers of anti-Abeta antibody, which in turn inhibited accumulation of Abeta pathology in the brains of older mice. Importantly, vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages.

Conclusions: Data from this transitional pre-clinical study suggest that our DNA epitope vaccine could be used as a safe and effective strategy for AD therapy. Future safety and immunology studies in large animals with the goal to achieve effective humoral immunity without adverse effects should help to translate this study to human clinical trials.

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Decrease in the levels of phosphorylated tau detected in the brains of vaccinated mice was not statistically significant.A) Image analysis of immunohistochemical staining demonstrates no differences in the levels of early-stage phosphorylated tau (AT100) in the hemibrains of vaccinated and control mice. Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm). B) Image analysis of immunohistochemical staining demonstrates no differences in the levels of mid-stage phosphorylated tau (AT8) in the hemibrains of vaccinated and control mice Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm). C) Image analysis of immunohistochemical staining demonstrates no differences in the levels of late-stage phosphorylated tau (PHF) in the hemibrains of vaccinated and control mice Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm).
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pone-0002124-g008: Decrease in the levels of phosphorylated tau detected in the brains of vaccinated mice was not statistically significant.A) Image analysis of immunohistochemical staining demonstrates no differences in the levels of early-stage phosphorylated tau (AT100) in the hemibrains of vaccinated and control mice. Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm). B) Image analysis of immunohistochemical staining demonstrates no differences in the levels of mid-stage phosphorylated tau (AT8) in the hemibrains of vaccinated and control mice Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm). C) Image analysis of immunohistochemical staining demonstrates no differences in the levels of late-stage phosphorylated tau (PHF) in the hemibrains of vaccinated and control mice Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm).

Mentions: Even though Aβ deposition may be the primary event in AD pathogenesis, it is clear that tau pathology also plays an important role in the progression of this disease [37]. Current data suggest that Aβ pathology emerges prior to tau pathology and may accelerate neurofibrillary tangle (NFT) formation [38], [39]. More recently, it was shown that early-, but not mid- and late-stage tau pathology could be significantly reduced in very old 3xTg-AD mice following active or passive vaccination [40]. We did not observe changes in the number of HT-7 positive neurons indicating that vaccination did not decrease total tau accumulation (Figure 7A). Likewise, we did not observe a significant reduction in early-(AT100), mid-(AT8), and late-(PHF-1) levels of hyperphosphorylated tau after DNA vaccination (Figure 8). To confirm this data, we also used more sensitive quantitative ELISA method and demonstrated that the levels of soluble tau were unaffected by DNA vaccination (Figure 7B). Although, concentration of insoluble tau decreased in brains of vaccinated animals compared with that of control mice, this change was not significant mainly due to a large variability of tau pathology in individual animals (Figure 7C). Thus, we concluded that even though tau burden decreased in immune 3xTg-AD mice, this change was not significant.


Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy.

Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud PB, Head E, Biragyn A, Cribbs DH, Agadjanyan MG - PLoS ONE (2008)

Decrease in the levels of phosphorylated tau detected in the brains of vaccinated mice was not statistically significant.A) Image analysis of immunohistochemical staining demonstrates no differences in the levels of early-stage phosphorylated tau (AT100) in the hemibrains of vaccinated and control mice. Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm). B) Image analysis of immunohistochemical staining demonstrates no differences in the levels of mid-stage phosphorylated tau (AT8) in the hemibrains of vaccinated and control mice Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm). C) Image analysis of immunohistochemical staining demonstrates no differences in the levels of late-stage phosphorylated tau (PHF) in the hemibrains of vaccinated and control mice Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2358976&req=5

pone-0002124-g008: Decrease in the levels of phosphorylated tau detected in the brains of vaccinated mice was not statistically significant.A) Image analysis of immunohistochemical staining demonstrates no differences in the levels of early-stage phosphorylated tau (AT100) in the hemibrains of vaccinated and control mice. Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm). B) Image analysis of immunohistochemical staining demonstrates no differences in the levels of mid-stage phosphorylated tau (AT8) in the hemibrains of vaccinated and control mice Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm). C) Image analysis of immunohistochemical staining demonstrates no differences in the levels of late-stage phosphorylated tau (PHF) in the hemibrains of vaccinated and control mice Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm).
Mentions: Even though Aβ deposition may be the primary event in AD pathogenesis, it is clear that tau pathology also plays an important role in the progression of this disease [37]. Current data suggest that Aβ pathology emerges prior to tau pathology and may accelerate neurofibrillary tangle (NFT) formation [38], [39]. More recently, it was shown that early-, but not mid- and late-stage tau pathology could be significantly reduced in very old 3xTg-AD mice following active or passive vaccination [40]. We did not observe changes in the number of HT-7 positive neurons indicating that vaccination did not decrease total tau accumulation (Figure 7A). Likewise, we did not observe a significant reduction in early-(AT100), mid-(AT8), and late-(PHF-1) levels of hyperphosphorylated tau after DNA vaccination (Figure 8). To confirm this data, we also used more sensitive quantitative ELISA method and demonstrated that the levels of soluble tau were unaffected by DNA vaccination (Figure 7B). Although, concentration of insoluble tau decreased in brains of vaccinated animals compared with that of control mice, this change was not significant mainly due to a large variability of tau pathology in individual animals (Figure 7C). Thus, we concluded that even though tau burden decreased in immune 3xTg-AD mice, this change was not significant.

Bottom Line: The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Abeta antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response.Importantly, vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages.Data from this transitional pre-clinical study suggest that our DNA epitope vaccine could be used as a safe and effective strategy for AD therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, California, United States of America.

ABSTRACT

Background: The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Abeta antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response. To achieve this goal we have designed a prototype chemokine-based DNA epitope vaccine expressing a fusion protein that consists of 3 copies of the self-B cell epitope of Abeta(42) (Abeta(1-11)) , a non-self T helper cell epitope (PADRE), and macrophage-derived chemokine (MDC/CCL22) as a molecular adjuvant to promote a strong anti-inflammatory Th2 phenotype.

Methods and findings: We generated pMDC-3Abeta(1-11)-PADRE construct and immunized 3xTg-AD mouse model starting at age of 3-4 months old. We demonstrated that prophylactic immunizations with the DNA epitope vaccine generated a robust Th2 immune response that induced high titers of anti-Abeta antibody, which in turn inhibited accumulation of Abeta pathology in the brains of older mice. Importantly, vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages.

Conclusions: Data from this transitional pre-clinical study suggest that our DNA epitope vaccine could be used as a safe and effective strategy for AD therapy. Future safety and immunology studies in large animals with the goal to achieve effective humoral immunity without adverse effects should help to translate this study to human clinical trials.

Show MeSH
Related in: MedlinePlus