tau-targeted immunization impedes progression of neurofibrillary histopathology in aged p301l tau transgenic mice岁tau-targeted免疫阻碍进展的神经纤维组织病理学p301lτ转基因小鼠.pdfVIP

Tau-Targeted Immunization Impedes Progression of Neurofibrillary Histopathology in Aged P301L Tau Transgenic Mice 1 1,2 1 ¨ ¨ 2 1 Mian Bi , Arne Ittner , Yazi D. Ke , Jurgen Gotz , Lars M. Ittner * 1 Laboratory for Translational Neurodegeneration, Brain and Mind Research Institute, The University of Sydney, Camperdown, New South Wales, Australia, 2 Alzheimer’s and Parkinson’s Disease Laboratory, Brain and Mind Research Institute, The University of Sydney, Camperdown, New South Wales, Australia Abstract In Alzheimer’s disease (AD) brains, the microtubule-associated protein tau and amyloid-b (Ab) deposit as intracellular neurofibrillary tangles (NFTs) and extracellular plaques, respectively. Tau deposits are furthermore found in a significant number of frontotemporal dementia cases. These diseases are characterized by progressive neurodegeneration, the loss of intellectual capabilities and behavioral changes. Unfortunately, the currently available therapies are limited to symptomatic relief. While active immunization against Ab has shown efficacy in both various AD mouse models and patients with AD, immunization against pathogenic tau has only recently been shown to prevent pathology in young tau transgenic mice. However, if translated to humans, diagnosis and treatment would be routinely done when symptoms are overt, meaning that the histopathological changes have already progressed. Therefore, we used active immunization to target pathogenic tau in 4, 8, and 18 months-old P301L tau transgenic pR5 mice that have an onset of NFT pathology at 6 months of age. In all age groups, NFT pathology was significantly reduced in treated compared to control pR5 mice. Similarly, phosphorylation of tau at pathological sites was reduced. In addition, increased as