Active full-length DNA Aβ42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology

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Abstract

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 (Aβ42) 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 Aβ42 immunotherapy were compared with brains from age- and gender-matched transgenic Aβ42 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 Aβ42 peptide and a 25-50% reduction of total tau and different phosphorylated tau molecules in the DNA Aβ42 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 Aβ42 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 Aβ42 peptide immunization in patients with AD (AN1792).

Original languageEnglish (US)
Number of pages1
JournalAlzheimer's research & therapy
Volume10
Issue number1
DOIs
StatePublished - Nov 20 2018

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Amyloid
Immunization
Alzheimer Disease
Pathology
Peptides
DNA
Brain
Enzyme-Linked Immunosorbent Assay
Immunotherapy
Phosphotransferases
Western Blotting
tau Proteins
Neurofibrillary Tangles
Amyloid Plaques
Protein Kinases
Transgenic Mice
Antibody Formation
Dementia
Anti-Idiotypic Antibodies
Histology

Keywords

  • Alzheimer’s disease
  • Amyloid-β
  • Aβ oligomer
  • DNA vaccination
  • Immunotherapy
  • Tau
  • Tau kinases

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience

Cite this

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title = "Active full-length DNA Aβ42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology",
abstract = "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 (Aβ42) 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 Aβ42 immunotherapy were compared with brains from age- and gender-matched transgenic Aβ42 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 Aβ42 peptide and a 25-50{\%} reduction of total tau and different phosphorylated tau molecules in the DNA Aβ42 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 Aβ42 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 Aβ42 peptide immunization in patients with AD (AN1792).",
keywords = "Alzheimer’s disease, Amyloid-β, Aβ oligomer, DNA vaccination, Immunotherapy, Tau, Tau kinases",
author = "Rosenberg, {Roger N} and Min Fu and Washington, {Doris L}",
year = "2018",
month = "11",
day = "20",
doi = "10.1186/s13195-018-0441-4",
language = "English (US)",
volume = "10",
journal = "Alzheimer's Research and Therapy",
issn = "1758-9193",
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TY - JOUR

T1 - Active full-length DNA Aβ42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology

AU - Rosenberg, Roger N

AU - Fu, Min

AU - Washington, Doris L

PY - 2018/11/20

Y1 - 2018/11/20

N2 - 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 (Aβ42) 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 Aβ42 immunotherapy were compared with brains from age- and gender-matched transgenic Aβ42 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 Aβ42 peptide and a 25-50% reduction of total tau and different phosphorylated tau molecules in the DNA Aβ42 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 Aβ42 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 Aβ42 peptide immunization in patients with AD (AN1792).

AB - 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 (Aβ42) 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 Aβ42 immunotherapy were compared with brains from age- and gender-matched transgenic Aβ42 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 Aβ42 peptide and a 25-50% reduction of total tau and different phosphorylated tau molecules in the DNA Aβ42 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 Aβ42 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 Aβ42 peptide immunization in patients with AD (AN1792).

KW - Alzheimer’s disease

KW - Amyloid-β

KW - Aβ oligomer

KW - DNA vaccination

KW - Immunotherapy

KW - Tau

KW - Tau kinases

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U2 - 10.1186/s13195-018-0441-4

DO - 10.1186/s13195-018-0441-4

M3 - Article

VL - 10

JO - Alzheimer's Research and Therapy

JF - Alzheimer's Research and Therapy

SN - 1758-9193

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ER -