1. Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model.
- Author
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Boutajangout A, Quartermain D, and Sigurdsson EM
- Subjects
- Alzheimer Disease blood, Alzheimer Disease genetics, Amyloid beta-Peptides genetics, Amyloid beta-Peptides metabolism, Animals, Antibodies blood, Antibodies therapeutic use, Behavior, Animal physiology, Brain metabolism, Brain pathology, DNA-Binding Proteins, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay methods, Female, Gliosis etiology, Humans, Male, Maze Learning physiology, Memory Disorders etiology, Memory Disorders immunology, Mice, Mice, Transgenic, Motor Activity genetics, Motor Activity immunology, Mutation genetics, Peptide Fragments genetics, Peptide Fragments metabolism, Polycomb-Group Proteins, Presenilin-1 genetics, Psychomotor Performance drug effects, Recognition, Psychology physiology, Rotarod Performance Test, Statistics, Nonparametric, Transcription Factors metabolism, tau Proteins genetics, Alzheimer Disease complications, Alzheimer Disease immunology, Cognition Disorders etiology, Cognition Disorders immunology, Cognition Disorders therapy, Immunotherapy methods, Mutation immunology, tau Proteins immunology
- Abstract
Harnessing the immune system to clear protein aggregates is emerging as a promising approach to treat various neurodegenerative diseases. In Alzheimer's disease (AD), several clinical trials are ongoing using active and passive immunotherapy targeting the amyloid-β (Aβ) peptide. Limited emphasis has been put into clearing tau/tangle pathology, another major hallmark of the disease. Recent findings from the first Aβ vaccination trial suggest that this approach has limited effect on tau pathology and that Aβ plaque clearance may not halt or slow the progression of dementia in individuals with mild-to-moderate AD. To assess within a reasonable timeframe whether targeting tau pathology with immunotherapy could prevent cognitive decline, we developed a new model with accelerated tangle development. It was generated by crossing available strains that express all six human tau isoforms and the M146L presenilin mutation. Here, we show that this unique approach completely prevents severe cognitive impairment in three different tests. This remarkable effect correlated well with extensive clearance of abnormal tau within the brain. Overall, our findings indicate that immunotherapy targeting pathological tau is very feasible for tauopathies, and should be assessed in clinical trials in the near future.
- Published
- 2010
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