Active full-length DNA $ Aβ_{42} $ immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology
Background Alzheimer’s disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain si...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Rosenberg, Roger N. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2018 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s). 2018 |
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| Übergeordnetes Werk: |
Enthalten in: Alzheimer's research & therapy - London : BioMed Central, 2009, 10(2018), 1 vom: 20. Nov. |
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| Übergeordnetes Werk: |
volume:10 ; year:2018 ; number:1 ; day:20 ; month:11 |
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| DOI / URN: |
10.1186/s13195-018-0441-4 |
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| Katalog-ID: |
SPR030864712 |
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| 520 | |a Background Alzheimer’s disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-β peptide 1–42 ($ Aβ_{42} $) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. Methods Immune responses were monitored by enzyme-linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA $ Aβ_{42} $ immunotherapy were compared with brains from age- and gender-matched transgenic $ Aβ_{42} $ peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates. Results Quantitative ELISA showed a 40% reduction of $ Aβ_{42} $ peptide and a 25–50% reduction of total tau and different phosphorylated tau molecules in the DNA $ Aβ_{42} $ trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Aβ peptide reductions in the brain were due to the anti-Aβ antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aβ in the brain resulting in less tau kinase activation. Conclusions The significance of these findings is that DNA $ Aβ_{42} $ trimer immunotherapy targets two major pathologies in AD—amyloid plaques and neurofibrillary tangles—in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active $ Aβ_{42} $ peptide immunization in patients with AD (AN1792). | ||
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10.1186/s13195-018-0441-4 doi (DE-627)SPR030864712 (SPR)s13195-018-0441-4-e DE-627 ger DE-627 rakwb eng Rosenberg, Roger N. verfasserin aut Active full-length DNA $ Aβ_{42} $ immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Alzheimer’s disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-β peptide 1–42 ($ Aβ_{42} $) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. Methods Immune responses were monitored by enzyme-linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA $ Aβ_{42} $ immunotherapy were compared with brains from age- and gender-matched transgenic $ Aβ_{42} $ peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates. Results Quantitative ELISA showed a 40% reduction of $ Aβ_{42} $ peptide and a 25–50% reduction of total tau and different phosphorylated tau molecules in the DNA $ Aβ_{42} $ trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Aβ peptide reductions in the brain were due to the anti-Aβ antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aβ in the brain resulting in less tau kinase activation. Conclusions The significance of these findings is that DNA $ Aβ_{42} $ trimer immunotherapy targets two major pathologies in AD—amyloid plaques and neurofibrillary tangles—in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active $ Aβ_{42} $ peptide immunization in patients with AD (AN1792). Alzheimer’s disease (dpeaa)DE-He213 Immunotherapy (dpeaa)DE-He213 DNA vaccination (dpeaa)DE-He213 Amyloid-β (dpeaa)DE-He213 Aβ oligomer (dpeaa)DE-He213 Tau (dpeaa)DE-He213 Tau kinases (dpeaa)DE-He213 Fu, Min aut Lambracht-Washington, Doris (orcid)0000-0002-3161-9207 aut Enthalten in Alzheimer's research & therapy London : BioMed Central, 2009 10(2018), 1 vom: 20. Nov. (DE-627)605683557 (DE-600)2506521-X 1758-9193 nnns volume:10 year:2018 number:1 day:20 month:11 https://dx.doi.org/10.1186/s13195-018-0441-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 20 11 |
| spelling |
10.1186/s13195-018-0441-4 doi (DE-627)SPR030864712 (SPR)s13195-018-0441-4-e DE-627 ger DE-627 rakwb eng Rosenberg, Roger N. verfasserin aut Active full-length DNA $ Aβ_{42} $ immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Alzheimer’s disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-β peptide 1–42 ($ Aβ_{42} $) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. Methods Immune responses were monitored by enzyme-linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA $ Aβ_{42} $ immunotherapy were compared with brains from age- and gender-matched transgenic $ Aβ_{42} $ peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates. Results Quantitative ELISA showed a 40% reduction of $ Aβ_{42} $ peptide and a 25–50% reduction of total tau and different phosphorylated tau molecules in the DNA $ Aβ_{42} $ trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Aβ peptide reductions in the brain were due to the anti-Aβ antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aβ in the brain resulting in less tau kinase activation. Conclusions The significance of these findings is that DNA $ Aβ_{42} $ trimer immunotherapy targets two major pathologies in AD—amyloid plaques and neurofibrillary tangles—in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active $ Aβ_{42} $ peptide immunization in patients with AD (AN1792). Alzheimer’s disease (dpeaa)DE-He213 Immunotherapy (dpeaa)DE-He213 DNA vaccination (dpeaa)DE-He213 Amyloid-β (dpeaa)DE-He213 Aβ oligomer (dpeaa)DE-He213 Tau (dpeaa)DE-He213 Tau kinases (dpeaa)DE-He213 Fu, Min aut Lambracht-Washington, Doris (orcid)0000-0002-3161-9207 aut Enthalten in Alzheimer's research & therapy London : BioMed Central, 2009 10(2018), 1 vom: 20. Nov. (DE-627)605683557 (DE-600)2506521-X 1758-9193 nnns volume:10 year:2018 number:1 day:20 month:11 https://dx.doi.org/10.1186/s13195-018-0441-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 20 11 |
| allfields_unstemmed |
10.1186/s13195-018-0441-4 doi (DE-627)SPR030864712 (SPR)s13195-018-0441-4-e DE-627 ger DE-627 rakwb eng Rosenberg, Roger N. verfasserin aut Active full-length DNA $ Aβ_{42} $ immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Alzheimer’s disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-β peptide 1–42 ($ Aβ_{42} $) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. Methods Immune responses were monitored by enzyme-linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA $ Aβ_{42} $ immunotherapy were compared with brains from age- and gender-matched transgenic $ Aβ_{42} $ peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates. Results Quantitative ELISA showed a 40% reduction of $ Aβ_{42} $ peptide and a 25–50% reduction of total tau and different phosphorylated tau molecules in the DNA $ Aβ_{42} $ trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Aβ peptide reductions in the brain were due to the anti-Aβ antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aβ in the brain resulting in less tau kinase activation. Conclusions The significance of these findings is that DNA $ Aβ_{42} $ trimer immunotherapy targets two major pathologies in AD—amyloid plaques and neurofibrillary tangles—in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active $ Aβ_{42} $ peptide immunization in patients with AD (AN1792). Alzheimer’s disease (dpeaa)DE-He213 Immunotherapy (dpeaa)DE-He213 DNA vaccination (dpeaa)DE-He213 Amyloid-β (dpeaa)DE-He213 Aβ oligomer (dpeaa)DE-He213 Tau (dpeaa)DE-He213 Tau kinases (dpeaa)DE-He213 Fu, Min aut Lambracht-Washington, Doris (orcid)0000-0002-3161-9207 aut Enthalten in Alzheimer's research & therapy London : BioMed Central, 2009 10(2018), 1 vom: 20. Nov. (DE-627)605683557 (DE-600)2506521-X 1758-9193 nnns volume:10 year:2018 number:1 day:20 month:11 https://dx.doi.org/10.1186/s13195-018-0441-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 20 11 |
| allfieldsGer |
10.1186/s13195-018-0441-4 doi (DE-627)SPR030864712 (SPR)s13195-018-0441-4-e DE-627 ger DE-627 rakwb eng Rosenberg, Roger N. verfasserin aut Active full-length DNA $ Aβ_{42} $ immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Alzheimer’s disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-β peptide 1–42 ($ Aβ_{42} $) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. Methods Immune responses were monitored by enzyme-linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA $ Aβ_{42} $ immunotherapy were compared with brains from age- and gender-matched transgenic $ Aβ_{42} $ peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates. Results Quantitative ELISA showed a 40% reduction of $ Aβ_{42} $ peptide and a 25–50% reduction of total tau and different phosphorylated tau molecules in the DNA $ Aβ_{42} $ trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Aβ peptide reductions in the brain were due to the anti-Aβ antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aβ in the brain resulting in less tau kinase activation. Conclusions The significance of these findings is that DNA $ Aβ_{42} $ trimer immunotherapy targets two major pathologies in AD—amyloid plaques and neurofibrillary tangles—in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active $ Aβ_{42} $ peptide immunization in patients with AD (AN1792). Alzheimer’s disease (dpeaa)DE-He213 Immunotherapy (dpeaa)DE-He213 DNA vaccination (dpeaa)DE-He213 Amyloid-β (dpeaa)DE-He213 Aβ oligomer (dpeaa)DE-He213 Tau (dpeaa)DE-He213 Tau kinases (dpeaa)DE-He213 Fu, Min aut Lambracht-Washington, Doris (orcid)0000-0002-3161-9207 aut Enthalten in Alzheimer's research & therapy London : BioMed Central, 2009 10(2018), 1 vom: 20. Nov. (DE-627)605683557 (DE-600)2506521-X 1758-9193 nnns volume:10 year:2018 number:1 day:20 month:11 https://dx.doi.org/10.1186/s13195-018-0441-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 20 11 |
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10.1186/s13195-018-0441-4 doi (DE-627)SPR030864712 (SPR)s13195-018-0441-4-e DE-627 ger DE-627 rakwb eng Rosenberg, Roger N. verfasserin aut Active full-length DNA $ Aβ_{42} $ immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Alzheimer’s disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-β peptide 1–42 ($ Aβ_{42} $) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. Methods Immune responses were monitored by enzyme-linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA $ Aβ_{42} $ immunotherapy were compared with brains from age- and gender-matched transgenic $ Aβ_{42} $ peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates. Results Quantitative ELISA showed a 40% reduction of $ Aβ_{42} $ peptide and a 25–50% reduction of total tau and different phosphorylated tau molecules in the DNA $ Aβ_{42} $ trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Aβ peptide reductions in the brain were due to the anti-Aβ antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aβ in the brain resulting in less tau kinase activation. Conclusions The significance of these findings is that DNA $ Aβ_{42} $ trimer immunotherapy targets two major pathologies in AD—amyloid plaques and neurofibrillary tangles—in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active $ Aβ_{42} $ peptide immunization in patients with AD (AN1792). Alzheimer’s disease (dpeaa)DE-He213 Immunotherapy (dpeaa)DE-He213 DNA vaccination (dpeaa)DE-He213 Amyloid-β (dpeaa)DE-He213 Aβ oligomer (dpeaa)DE-He213 Tau (dpeaa)DE-He213 Tau kinases (dpeaa)DE-He213 Fu, Min aut Lambracht-Washington, Doris (orcid)0000-0002-3161-9207 aut Enthalten in Alzheimer's research & therapy London : BioMed Central, 2009 10(2018), 1 vom: 20. Nov. (DE-627)605683557 (DE-600)2506521-X 1758-9193 nnns volume:10 year:2018 number:1 day:20 month:11 https://dx.doi.org/10.1186/s13195-018-0441-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 20 11 |
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Rosenberg, Roger N. misc Alzheimer’s disease misc Immunotherapy misc DNA vaccination misc Amyloid-β misc Aβ oligomer misc Tau misc Tau kinases Active full-length DNA $ Aβ_{42} $ immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology |
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Active full-length DNA $ Aβ_{42} $ immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology Alzheimer’s disease (dpeaa)DE-He213 Immunotherapy (dpeaa)DE-He213 DNA vaccination (dpeaa)DE-He213 Amyloid-β (dpeaa)DE-He213 Aβ oligomer (dpeaa)DE-He213 Tau (dpeaa)DE-He213 Tau kinases (dpeaa)DE-He213 |
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Active full-length DNA $ Aβ_{42} $ immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology |
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Background Alzheimer’s disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-β peptide 1–42 ($ Aβ_{42} $) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. Methods Immune responses were monitored by enzyme-linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA $ Aβ_{42} $ immunotherapy were compared with brains from age- and gender-matched transgenic $ Aβ_{42} $ peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates. Results Quantitative ELISA showed a 40% reduction of $ Aβ_{42} $ peptide and a 25–50% reduction of total tau and different phosphorylated tau molecules in the DNA $ Aβ_{42} $ trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Aβ peptide reductions in the brain were due to the anti-Aβ antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aβ in the brain resulting in less tau kinase activation. Conclusions The significance of these findings is that DNA $ Aβ_{42} $ trimer immunotherapy targets two major pathologies in AD—amyloid plaques and neurofibrillary tangles—in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active $ Aβ_{42} $ peptide immunization in patients with AD (AN1792). © The Author(s). 2018 |
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Background Alzheimer’s disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-β peptide 1–42 ($ Aβ_{42} $) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. Methods Immune responses were monitored by enzyme-linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA $ Aβ_{42} $ immunotherapy were compared with brains from age- and gender-matched transgenic $ Aβ_{42} $ peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates. Results Quantitative ELISA showed a 40% reduction of $ Aβ_{42} $ peptide and a 25–50% reduction of total tau and different phosphorylated tau molecules in the DNA $ Aβ_{42} $ trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Aβ peptide reductions in the brain were due to the anti-Aβ antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aβ in the brain resulting in less tau kinase activation. Conclusions The significance of these findings is that DNA $ Aβ_{42} $ trimer immunotherapy targets two major pathologies in AD—amyloid plaques and neurofibrillary tangles—in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active $ Aβ_{42} $ peptide immunization in patients with AD (AN1792). © The Author(s). 2018 |
| abstract_unstemmed |
Background Alzheimer’s disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-β peptide 1–42 ($ Aβ_{42} $) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. Methods Immune responses were monitored by enzyme-linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA $ Aβ_{42} $ immunotherapy were compared with brains from age- and gender-matched transgenic $ Aβ_{42} $ peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates. Results Quantitative ELISA showed a 40% reduction of $ Aβ_{42} $ peptide and a 25–50% reduction of total tau and different phosphorylated tau molecules in the DNA $ Aβ_{42} $ trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Aβ peptide reductions in the brain were due to the anti-Aβ antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aβ in the brain resulting in less tau kinase activation. Conclusions The significance of these findings is that DNA $ Aβ_{42} $ trimer immunotherapy targets two major pathologies in AD—amyloid plaques and neurofibrillary tangles—in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active $ Aβ_{42} $ peptide immunization in patients with AD (AN1792). © The Author(s). 2018 |
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Active full-length DNA $ Aβ_{42} $ immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology |
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Fu, Min Lambracht-Washington, Doris |
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