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

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-beta peptide 1-42 (A beta(42)) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. 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 A beta(42) immunotherapy were compared with brains from age- and gender-matched transgenic A beta(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. Quantitative ELISA showed a 40% reduction of A beta(42) peptide and a 25-50% reduction of total tau and different phosphorylated tau molecules in the DNA A beta(42) trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and A beta peptide reductions in the brain were due to the anti-A beta antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less A beta in the brain resulting in less tau kinase activation. The significance of these findings is that DNA A beta(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 A beta(42) peptide immunization in patients with AD (AN1792).