The neurofibrillary-tangles (NTFs), characteristic of tauopathies including Alzheimer's-disease (AD), are the pathological features which correlate best with dementia. The objective of our study was to generate an authentic transgenic (tg) animal model for NFT pathology in tauopathy/AD. Previous NFT-tg mice were driven by non-related/non-homologous promoters. Our strategy was to use the natural tau promoter for expressing the human-tau (htau) gene with two mutations K257T/P301S (double mutant, DM) associated with severe phenotypes of frontotemporal-dementia in humans. Cellular, biochemical, behavioral and electrophysiological studies were subsequently conducted. The tg mice showed a tolerated physiological level of the DM-htau protein, mostly in cortex and hippocampus. The mice demonstrated tauopathy-like characteristics, which increased with age, that included NFT-related pathology, astrogliosis, argyrophilic plaque-like (amyloid-free) structures in brain, with memory deficits and signs of anxiety. Moreover, the tg mice showed a robust synaptic plasticity deficit selectively expressed in a severe impairment in their ability to maintain hippocampal long-term-potentiation (LTP) in response to stimulation of the perforant path, providing evidence that "tau-pathology only" is sufficient to cause this memory and learning-associated deficit. This is a unique mutant-htau-tg model which presents a wide spectrum of features characteristic of tauopathy/AD, which does not show unrelated motor deficits described in other models of tauopathy. In addition, expressing the DM-htau in a neuronal cell model resulted in tau-aggregation, as well as impaired microtubule arrangement. Both animal and cell models, which were regulated under the natural tau promoter (of rat origin), provide authentic and reliable models for tauopathy, and offer valuable tools for understanding the molecular events underlying tauopathies including AD.
Bibliographical noteFunding Information:
This work in the Department of Neurology, Hadassah University Hospital, Jerusalem, was supported in part by the Lena P. Havey Endowment Fund for Research in Neurology, and by the fund of the Woman Health-Hadassah. We thank Fanny Baitscher for the technical assistance. We also thank Dr. Bentzi Zuberi from the Tg-Unit, Dr. Ezra Rahamim from the EM-Unit, and Tali Bedolach from the Statistics Unit, in the School of Medicine, Hadassah. The work was also partially supported by Israel Science Foundation, Mario Negri Foundation, and by the Benoziyo Center for Neurological Diseases of the WIS grants to IG. IG holds the Sophie and Richard S. Richards Professorial Chair in Cancer Research. We also thank Prof. Karen Duff from the Nathan Kline Institute New York University, for the analysis of amyloid-beta in brains by ELISA.
- Homologous tau promoter
- Neurofibrillary tangles
- Transgenic mice
ASJC Scopus subject areas
- Developmental Neuroscience