A novel transgenic mouse expressing double mutant tau driven by its natural promoter exhibits tauopathy characteristics

Hanna Rosenmann; Nikolaos Grigoriadis; Hila Eldar-Levy; Avi Avital; Lea Rozenstein; Olga Touloumi; Leah Behar; Tamir Ben-Hur; Yosefa Avraham; Eliot Berry; Menahem Segal; Irith Ginzburg; Oded Abramsky

doi:10.1016/j.expneurol.2008.03.007

A novel transgenic mouse expressing double mutant tau driven by its natural promoter exhibits tauopathy characteristics

Hanna Rosenmann, Nikolaos Grigoriadis, Hila Eldar-Levy, Avi Avital, Lea Rozenstein, Olga Touloumi, Leah Behar, Tamir Ben-Hur, Yosefa Avraham, Eliot Berry, Menahem Segal, Irith Ginzburg, Oded Abramsky

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	71-84
Number of pages	14
Journal	Experimental Neurology
Volume	212
Issue number	1
DOIs	https://doi.org/10.1016/j.expneurol.2008.03.007
State	Published - Jul 2008
Externally published	Yes

Bibliographical note

Funding 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.

Keywords

Homologous tau promoter
LTP
Mutation
Neurofibrillary tangles
Tau
Tauopathy
Transgenic mice

ASJC Scopus subject areas

Neurology
Developmental Neuroscience

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10.1016/j.expneurol.2008.03.007

Cite this

Rosenmann, H., Grigoriadis, N., Eldar-Levy, H., Avital, A., Rozenstein, L., Touloumi, O., Behar, L., Ben-Hur, T., Avraham, Y., Berry, E., Segal, M., Ginzburg, I., & Abramsky, O. (2008). A novel transgenic mouse expressing double mutant tau driven by its natural promoter exhibits tauopathy characteristics. Experimental Neurology, 212(1), 71-84. https://doi.org/10.1016/j.expneurol.2008.03.007

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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.",

keywords = "Homologous tau promoter, LTP, Mutation, Neurofibrillary tangles, Tau, Tauopathy, Transgenic mice",

author = "Hanna Rosenmann and Nikolaos Grigoriadis and Hila Eldar-Levy and Avi Avital and Lea Rozenstein and Olga Touloumi and Leah Behar and Tamir Ben-Hur and Yosefa Avraham and Eliot Berry and Menahem Segal and Irith Ginzburg and Oded Abramsky",

note = "Funding 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.",

year = "2008",

month = jul,

doi = "10.1016/j.expneurol.2008.03.007",

language = "English",

volume = "212",

pages = "71--84",

journal = "Experimental Neurology",

issn = "0014-4886",

publisher = "Academic Press Inc.",

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Rosenmann, H, Grigoriadis, N, Eldar-Levy, H, Avital, A, Rozenstein, L, Touloumi, O, Behar, L, Ben-Hur, T, Avraham, Y, Berry, E, Segal, M, Ginzburg, I & Abramsky, O 2008, 'A novel transgenic mouse expressing double mutant tau driven by its natural promoter exhibits tauopathy characteristics', Experimental Neurology, vol. 212, no. 1, pp. 71-84. https://doi.org/10.1016/j.expneurol.2008.03.007

TY - JOUR

T1 - A novel transgenic mouse expressing double mutant tau driven by its natural promoter exhibits tauopathy characteristics

AU - Rosenmann, Hanna

AU - Grigoriadis, Nikolaos

AU - Eldar-Levy, Hila

AU - Avital, Avi

AU - Rozenstein, Lea

AU - Touloumi, Olga

AU - Behar, Leah

AU - Ben-Hur, Tamir

AU - Avraham, Yosefa

AU - Berry, Eliot

AU - Segal, Menahem

AU - Ginzburg, Irith

AU - Abramsky, Oded

N1 - Funding 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.

PY - 2008/7

Y1 - 2008/7

N2 - 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.

AB - 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.

KW - Homologous tau promoter

KW - LTP

KW - Mutation

KW - Neurofibrillary tangles

KW - Tau

KW - Tauopathy

KW - Transgenic mice

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DO - 10.1016/j.expneurol.2008.03.007

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AN - SCOPUS:44949185340

SN - 0014-4886

VL - 212

SP - 71

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JO - Experimental Neurology

JF - Experimental Neurology

IS - 1

ER -

A novel transgenic mouse expressing double mutant tau driven by its natural promoter exhibits tauopathy characteristics

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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