Differential accumulation of tau pathology between reciprocal F1 hybrids of rTg4510 mice

Abstract Tau, a family of microtubule-associated proteins, forms abnormal intracellular inclusions, so-called tau pathology, in a range of neurodegenerative diseases collectively known as tauopathies. The rTg4510 mouse model is a well-characterized bitransgenic F1 hybrid mouse model of tauopathy, wh...

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Autores principales:	Daijiro Yanagisawa, Hamizah Shahirah Hamezah, Aslina Pahrudin Arrozi, Ikuo Tooyama
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dca4a4546b4540bb90b7036201aad0c5
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spelling	oai:doaj.org-article:dca4a4546b4540bb90b7036201aad0c52021-12-02T16:51:31ZDifferential accumulation of tau pathology between reciprocal F1 hybrids of rTg4510 mice10.1038/s41598-021-89142-22045-2322https://doaj.org/article/dca4a4546b4540bb90b7036201aad0c52021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89142-2https://doaj.org/toc/2045-2322Abstract Tau, a family of microtubule-associated proteins, forms abnormal intracellular inclusions, so-called tau pathology, in a range of neurodegenerative diseases collectively known as tauopathies. The rTg4510 mouse model is a well-characterized bitransgenic F1 hybrid mouse model of tauopathy, which was obtained by crossing a Camk2α-tTA mouse line (on a C57BL/6 J background) with a tetO-MAPT*P301L mouse line (on a FVB/NJ background). The aim of this study was to investigate the effects of the genetic background and sex on the accumulation of tau pathology in reciprocal F1 hybrids of rTg4510 mice, i.e., rTg4510 on the (C57BL/6 J × FVB/NJ)F1 background (rTg4510_CxF) and on the (FVB/NJ × C57BL/6 J)F1 background (rTg4510_FxC). As compared with rTg4510_CxF mice, the rTg4510_FxC mice showed marked levels of tau pathology in the forebrain. Biochemical analyses indicated that the accumulation of abnormal tau species was accelerated in rTg4510_FxC mice. There were strong effects of the genetic background on the differential accumulation of tau pathology in rTg4510 mice, while sex had no apparent effect. Interestingly, midline-1 (Mid1) was identified as a candidate gene associated with this difference and exhibited significant up/downregulation according to the genetic background. Mid1 silencing with siRNA induced pathological phosphorylation of tau in HEK293T cells that stably expressed human tau with the P301L mutation, suggesting the role of Mid1 in pathological alterations of tau. Elucidation of the underlying mechanisms will provide novel insights into the accumulation of tau pathology and is expected to be especially informative to researchers for the continued development of therapeutic interventions for tauopathies.Daijiro YanagisawaHamizah Shahirah HamezahAslina Pahrudin ArroziIkuo TooyamaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Daijiro Yanagisawa Hamizah Shahirah Hamezah Aslina Pahrudin Arrozi Ikuo Tooyama Differential accumulation of tau pathology between reciprocal F1 hybrids of rTg4510 mice
description	Abstract Tau, a family of microtubule-associated proteins, forms abnormal intracellular inclusions, so-called tau pathology, in a range of neurodegenerative diseases collectively known as tauopathies. The rTg4510 mouse model is a well-characterized bitransgenic F1 hybrid mouse model of tauopathy, which was obtained by crossing a Camk2α-tTA mouse line (on a C57BL/6 J background) with a tetO-MAPT*P301L mouse line (on a FVB/NJ background). The aim of this study was to investigate the effects of the genetic background and sex on the accumulation of tau pathology in reciprocal F1 hybrids of rTg4510 mice, i.e., rTg4510 on the (C57BL/6 J × FVB/NJ)F1 background (rTg4510_CxF) and on the (FVB/NJ × C57BL/6 J)F1 background (rTg4510_FxC). As compared with rTg4510_CxF mice, the rTg4510_FxC mice showed marked levels of tau pathology in the forebrain. Biochemical analyses indicated that the accumulation of abnormal tau species was accelerated in rTg4510_FxC mice. There were strong effects of the genetic background on the differential accumulation of tau pathology in rTg4510 mice, while sex had no apparent effect. Interestingly, midline-1 (Mid1) was identified as a candidate gene associated with this difference and exhibited significant up/downregulation according to the genetic background. Mid1 silencing with siRNA induced pathological phosphorylation of tau in HEK293T cells that stably expressed human tau with the P301L mutation, suggesting the role of Mid1 in pathological alterations of tau. Elucidation of the underlying mechanisms will provide novel insights into the accumulation of tau pathology and is expected to be especially informative to researchers for the continued development of therapeutic interventions for tauopathies.
format	article
author	Daijiro Yanagisawa Hamizah Shahirah Hamezah Aslina Pahrudin Arrozi Ikuo Tooyama
author_facet	Daijiro Yanagisawa Hamizah Shahirah Hamezah Aslina Pahrudin Arrozi Ikuo Tooyama
author_sort	Daijiro Yanagisawa
title	Differential accumulation of tau pathology between reciprocal F1 hybrids of rTg4510 mice
title_short	Differential accumulation of tau pathology between reciprocal F1 hybrids of rTg4510 mice
title_full	Differential accumulation of tau pathology between reciprocal F1 hybrids of rTg4510 mice
title_fullStr	Differential accumulation of tau pathology between reciprocal F1 hybrids of rTg4510 mice
title_full_unstemmed	Differential accumulation of tau pathology between reciprocal F1 hybrids of rTg4510 mice
title_sort	differential accumulation of tau pathology between reciprocal f1 hybrids of rtg4510 mice
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/dca4a4546b4540bb90b7036201aad0c5
work_keys_str_mv	AT daijiroyanagisawa differentialaccumulationoftaupathologybetweenreciprocalf1hybridsofrtg4510mice AT hamizahshahirahhamezah differentialaccumulationoftaupathologybetweenreciprocalf1hybridsofrtg4510mice AT aslinapahrudinarrozi differentialaccumulationoftaupathologybetweenreciprocalf1hybridsofrtg4510mice AT ikuotooyama differentialaccumulationoftaupathologybetweenreciprocalf1hybridsofrtg4510mice
_version_	1718382948963581952

Differential accumulation of tau pathology between reciprocal F1 hybrids of rTg4510 mice

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