Differential neurotoxicity related to tetracycline transactivator and TDP-43 expression in conditional TDP-43 mouse model of frontotemporal lobar degeneration

L. Kukreja, R. Shahidehpour, G. Kim, J. Keegan, Katherine Rose Sadleir, T. Russell, John G Csernansky, Marek-Marsel Mesulam, Robert J Vassar, L. Wang, Hongxin Dong, Changiz Geula*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Frontotemporal lobar degeneration (FTLD) is among the most prevalent dementias of early-onset. Pathologically, FTLD presents with tauopathy or TAR DNA-binding protein 43 (TDP-43) proteinopathy. A biallelic mouse model of FTLD was produced on a mix FVB/ 129SVE background overexpressing wild-type human TDP-43 (hTDP-43) using tetracycline transactivator (tTA), a system widely used in mouse models of neurological disorders. tTA activates hTDP-43, which is placed downstream of the tetracycline response element. The original study on this transgenic mouse found hippocampal degeneration following hTDP-43 expression, but did not account for independent effects of tTA protein. Here, we initially analyzed the neurotoxic effects of tTA in postweaning age mice of either sex using immunostaining and area measurements of select brain regions. We observed tTA-dependent toxicity selectively in the hippocampus affecting the dentate gyrus significantly more than CA fields, whereas hTDP-43-dependent toxicity in bigenic mice occurred in most other cortical regions. Atrophy was associated with inflammation, activation of caspase-3, and loss of neurons. The atrophy associated with tTA expression was rescuable by the tetracycline analog, doxycycline, in the diet. MRI studies corroborated the patterns of atrophy. tTA-induced degeneration was strain-dependent and was rescued by moving the transgene onto a congenic C57BL/6 background. Despite significant hippocampal atrophy, behavioral tests in bigenic mice revealed no hippocampally mediated memory impairment. Significant atrophy in most cortical areas due solely to TDP-43 expression indicates that this mouse model remains useful for providing critical insight into co-occurrence of TDP-43 pathology, neurodegeneration, and behavioral deficits in FTLD.

Original languageEnglish (US)
Pages (from-to)6045-6062
Number of pages18
JournalJournal of Neuroscience
Volume38
Issue number27
DOIs
StatePublished - Jul 4 2018

Fingerprint

Frontotemporal Lobar Degeneration
Trans-Activators
DNA-Binding Proteins
Tetracycline
Atrophy
Tauopathies
mouse TDP-43 protein
Doxycycline
Dentate Gyrus
Response Elements
Nervous System Diseases
Transgenes
Caspase 3
Transgenic Mice
Dementia
Hippocampus
Pathology
Diet
Inflammation
Neurons

Keywords

  • Conditional transgenic
  • Doxycycline transducer toxicity
  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • TDP-43 toxicity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

@article{d68bc664a72248918ab56bf563db99a6,
title = "Differential neurotoxicity related to tetracycline transactivator and TDP-43 expression in conditional TDP-43 mouse model of frontotemporal lobar degeneration",
abstract = "Frontotemporal lobar degeneration (FTLD) is among the most prevalent dementias of early-onset. Pathologically, FTLD presents with tauopathy or TAR DNA-binding protein 43 (TDP-43) proteinopathy. A biallelic mouse model of FTLD was produced on a mix FVB/ 129SVE background overexpressing wild-type human TDP-43 (hTDP-43) using tetracycline transactivator (tTA), a system widely used in mouse models of neurological disorders. tTA activates hTDP-43, which is placed downstream of the tetracycline response element. The original study on this transgenic mouse found hippocampal degeneration following hTDP-43 expression, but did not account for independent effects of tTA protein. Here, we initially analyzed the neurotoxic effects of tTA in postweaning age mice of either sex using immunostaining and area measurements of select brain regions. We observed tTA-dependent toxicity selectively in the hippocampus affecting the dentate gyrus significantly more than CA fields, whereas hTDP-43-dependent toxicity in bigenic mice occurred in most other cortical regions. Atrophy was associated with inflammation, activation of caspase-3, and loss of neurons. The atrophy associated with tTA expression was rescuable by the tetracycline analog, doxycycline, in the diet. MRI studies corroborated the patterns of atrophy. tTA-induced degeneration was strain-dependent and was rescued by moving the transgene onto a congenic C57BL/6 background. Despite significant hippocampal atrophy, behavioral tests in bigenic mice revealed no hippocampally mediated memory impairment. Significant atrophy in most cortical areas due solely to TDP-43 expression indicates that this mouse model remains useful for providing critical insight into co-occurrence of TDP-43 pathology, neurodegeneration, and behavioral deficits in FTLD.",
keywords = "Conditional transgenic, Doxycycline transducer toxicity, Frontotemporal dementia, Frontotemporal lobar degeneration, TDP-43 toxicity",
author = "L. Kukreja and R. Shahidehpour and G. Kim and J. Keegan and Sadleir, {Katherine Rose} and T. Russell and Csernansky, {John G} and Marek-Marsel Mesulam and Vassar, {Robert J} and L. Wang and Hongxin Dong and Changiz Geula",
year = "2018",
month = "7",
day = "4",
doi = "10.1523/JNEUROSCI.1836-17.2018",
language = "English (US)",
volume = "38",
pages = "6045--6062",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "27",

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TY - JOUR

T1 - Differential neurotoxicity related to tetracycline transactivator and TDP-43 expression in conditional TDP-43 mouse model of frontotemporal lobar degeneration

AU - Kukreja, L.

AU - Shahidehpour, R.

AU - Kim, G.

AU - Keegan, J.

AU - Sadleir, Katherine Rose

AU - Russell, T.

AU - Csernansky, John G

AU - Mesulam, Marek-Marsel

AU - Vassar, Robert J

AU - Wang, L.

AU - Dong, Hongxin

AU - Geula, Changiz

PY - 2018/7/4

Y1 - 2018/7/4

N2 - Frontotemporal lobar degeneration (FTLD) is among the most prevalent dementias of early-onset. Pathologically, FTLD presents with tauopathy or TAR DNA-binding protein 43 (TDP-43) proteinopathy. A biallelic mouse model of FTLD was produced on a mix FVB/ 129SVE background overexpressing wild-type human TDP-43 (hTDP-43) using tetracycline transactivator (tTA), a system widely used in mouse models of neurological disorders. tTA activates hTDP-43, which is placed downstream of the tetracycline response element. The original study on this transgenic mouse found hippocampal degeneration following hTDP-43 expression, but did not account for independent effects of tTA protein. Here, we initially analyzed the neurotoxic effects of tTA in postweaning age mice of either sex using immunostaining and area measurements of select brain regions. We observed tTA-dependent toxicity selectively in the hippocampus affecting the dentate gyrus significantly more than CA fields, whereas hTDP-43-dependent toxicity in bigenic mice occurred in most other cortical regions. Atrophy was associated with inflammation, activation of caspase-3, and loss of neurons. The atrophy associated with tTA expression was rescuable by the tetracycline analog, doxycycline, in the diet. MRI studies corroborated the patterns of atrophy. tTA-induced degeneration was strain-dependent and was rescued by moving the transgene onto a congenic C57BL/6 background. Despite significant hippocampal atrophy, behavioral tests in bigenic mice revealed no hippocampally mediated memory impairment. Significant atrophy in most cortical areas due solely to TDP-43 expression indicates that this mouse model remains useful for providing critical insight into co-occurrence of TDP-43 pathology, neurodegeneration, and behavioral deficits in FTLD.

AB - Frontotemporal lobar degeneration (FTLD) is among the most prevalent dementias of early-onset. Pathologically, FTLD presents with tauopathy or TAR DNA-binding protein 43 (TDP-43) proteinopathy. A biallelic mouse model of FTLD was produced on a mix FVB/ 129SVE background overexpressing wild-type human TDP-43 (hTDP-43) using tetracycline transactivator (tTA), a system widely used in mouse models of neurological disorders. tTA activates hTDP-43, which is placed downstream of the tetracycline response element. The original study on this transgenic mouse found hippocampal degeneration following hTDP-43 expression, but did not account for independent effects of tTA protein. Here, we initially analyzed the neurotoxic effects of tTA in postweaning age mice of either sex using immunostaining and area measurements of select brain regions. We observed tTA-dependent toxicity selectively in the hippocampus affecting the dentate gyrus significantly more than CA fields, whereas hTDP-43-dependent toxicity in bigenic mice occurred in most other cortical regions. Atrophy was associated with inflammation, activation of caspase-3, and loss of neurons. The atrophy associated with tTA expression was rescuable by the tetracycline analog, doxycycline, in the diet. MRI studies corroborated the patterns of atrophy. tTA-induced degeneration was strain-dependent and was rescued by moving the transgene onto a congenic C57BL/6 background. Despite significant hippocampal atrophy, behavioral tests in bigenic mice revealed no hippocampally mediated memory impairment. Significant atrophy in most cortical areas due solely to TDP-43 expression indicates that this mouse model remains useful for providing critical insight into co-occurrence of TDP-43 pathology, neurodegeneration, and behavioral deficits in FTLD.

KW - Conditional transgenic

KW - Doxycycline transducer toxicity

KW - Frontotemporal dementia

KW - Frontotemporal lobar degeneration

KW - TDP-43 toxicity

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DO - 10.1523/JNEUROSCI.1836-17.2018

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JO - Journal of Neuroscience

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