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

Daijiro Yanagisawa,Aslina Pahrudin Arrozi,Ikuo Tooyama,Hamizah Shahirah Hamezah

doi:10.1038/s41598-021-89142-2

Daijiro Yanagisawa, Aslina Pahrudin Arrozi + Show 2 more

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https://doi.org/10.1038/s41598-021-89142-2

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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.

Highlights

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
We investigated tau pathology in reciprocal F1 hybrids of rTg4510 mice at 3 and 6 months of age
There was, a significant difference in Mid1 mRNA levels between the reciprocal F1 hybrids, and MID1 silencing with siRNA induced pathological phosphorylation of tau in HEK293T cells stably expressing human tau with the P301L mutation

Summary

Introduction

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 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). There were strong effects of the genetic background on the differential accumulation of tau pathology in rTg4510 mice, while sex had no apparent effect. In 1998, missense mutations of tau were identified in patients with frontotemporal dementia associated with parkinsonism linked to chromosome 178–10 This discovery demonstrated that the pathological abnormalities of tau can be a primary or even the sole cause of tauopathy. In the present study, the mechanisms underlying differential tau accumulation in rTg4510 mice were investigated, while focusing on the effects of the genetic background and sex. A deeper understanding of tau pathology will be useful for the development of therapeutic regimens for tauopathies

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