Alzheimer's disease (AD) is a devastating neurodegenerative disease pathologically characterized by the formation of two protein lesions, intracellular neurofibrillary tangles, composed of hyperphosphorylated tau and extracellular senile plaques composed of amyloid beta (Aβ) peptide. Earlier studies explored Aβ immunotherapy in transgenic mouse models with promising results. However, tau pathology better correlates with neurodegeneration and severity of dementia. Passive and active immunotherapy targeting tau pathology in a mutated tau mouse model resulted in a reduction of tangle counts and improved performance on tangle related motor tasks. However, there are no tau mutations in AD and these mice develop spinal cord and brainstem pathology, an anatomic distribution of tau pathology not seen in AD cases. The tau transgenic mouse model htau, develop age dependent tau pathology with a similar anatomical distribution as seen in AD. Due to the promising results of tau immunotherapy in mutant tau mouse models, we hypothesized that we would see a reduction in the insoluble fraction of tau following both active and passive immunotherapy in htau mice.
We have investigated the effects of active immunization with paired helical filament tau (PHF-tau), isolated from human Alzheimer's brains as the immunogen, as well as passive immunotherapy utilizing two tau antibodies. We have examined tau pathology in these hTau mice with carefully validated biochemical methods. Following active immunotherapy there was an observed decrease in levels of soluble pS202 and pT231 tau by ELISA. However, in htau mice passively immunized with the antibody, PHF1, there was an increase in total, pS202, pT231, and p396/404 tau in the insoluble fraction.
Our results suggest that active immunization strategies can reduce the burden of tau pathology in htau mice as demonstrated by the reduction of pS202 and pT231 tau. The passive immunotherapy results are surprising and the same treatments appear to have opposite effects in htau mice compared to P301L and P301S mice. Further work will be necessary to examine the possible causes of these elevated insoluble tau levels and why there are different results with the same treatment in different mouse models.
|Commitee:||Duff, Karen, Huang, Henry, Lipton, Michael, Segall, Jeffrey, Shafit-Zagardo, Bridget|
|School Location:||United States -- New York|
|Source:||DAI-B 74/05(E), Dissertation Abstracts International|
|Keywords:||Alzheimer's disease, Immunotherapy, PHF-tau, Tau|
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