title: A novel transgenic mouse expressing double mutant tau driven by its natural promoter exhibits tauopathy characteristics.
abstract: 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.
authors.affiliation: The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Medical Center, Jerusalem, Israel. rosenman@hadassah.org.il
authors.forename: Hanna
authors.initials: H
authors.lastname: Rosenmann
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Grigoriadis
authors.forename: Hila
authors.initials: H
authors.lastname: Eldar-Levy
authors.forename: Avi
authors.initials: A
authors.lastname: Avital
authors.forename: Lea
authors.initials: L
authors.lastname: Rozenstein
authors.forename: Olga
authors.initials: O
authors.lastname: Touloumi
authors.forename: Leah
authors.initials: L
authors.lastname: Behar
authors.forename: Tamir
authors.initials: T
authors.lastname: Ben-Hur
authors.forename: Yosefa
authors.initials: Y
authors.lastname: Avraham
authors.forename: Eliot
authors.initials: E
authors.lastname: Berry
authors.forename: Menahem
authors.initials: M
authors.lastname: Segal
authors.forename: Irith
authors.initials: I
authors.lastname: Ginzburg
authors.forename: Oded
authors.initials: O
authors.lastname: Abramsky
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D017774:Long-Term Potentiation / Q000235:genetics; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D024801:Tauopathies / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016875:tau Proteins