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 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).