Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs.

Naruhiko Sahara,Mutsuki Amano,Celeste M. Karch,Shin-ichi Hisanaga,Mari Nakamura,Taeko Kimura,Kozo Kaibuchi,Tomohiro Miyasaka,Hideyuki Okano,Seiji Shiozawa,Fumihiko Kisa,Takeshi Ikeuchi,Sumihiro Maeda,Hirotaka Watanabe,Sho Yoshimatsu,Akihiko Takashima,Daisuke Tsuboi

doi:10.1016/j.stemcr.2019.08.011

Abstract

SummaryMutations in the microtubule-associated protein tau (MAPT) gene are known to cause familial frontotemporal dementia (FTD). The R406W tau mutation is a unique missense mutation whose patients have been reported to exhibit Alzheimer’s disease (AD)-like phenotypes rather than the more typical FTD phenotypes. In this study, we established patient-derived induced pluripotent stem cell (iPSC) models to investigate the disease pathology induced by the R406W mutation. We generated iPSCs from patients and established isogenic lines using CRISPR/Cas9. The iPSCs were induced into cerebral organoids, which were dissociated into cortical neurons with high purity. In this neuronal culture, the mutant tau protein exhibited reduced phosphorylation levels and was increasingly fragmented by calpain. Furthermore, the mutant tau protein was mislocalized and the axons of the patient-derived neurons displayed morphological and functional abnormalities, which were rescued by microtubule stabilization. The findings of our study provide mechanistic insight into tau pathology and a potential for therapeutic intervention.

Highlights

Frontotemporal dementia (FTD) is one of the most common types of early-onset dementia after Alzheimer’s disease (AD)
Using neurons differentiated from patient-derived induced pluripotent stem cell (iPSC) and their corresponding isogenic lines, we identified the biochemical changes of tau induced by the R406W mutation and their effects at the cellular level
The patients had no other mutations besides the microtubule-associated protein tau (MAPT) R406W mutation, as previously confirmed (Ikeuchi et al, 2011)

Summary

Introduction

Frontotemporal dementia (FTD) is one of the most common types of early-onset dementia after Alzheimer’s disease (AD). The R406W missense mutation is one such pathological mutation located on exon 13 of the MAPT gene (Hutton et al, 1998; Rizzu et al, 1999; Van Swieten et al, 1999) Patients with this mutation have been reported to exhibit AD-like phenotypes: early memory impairment is a primary presenting feature, while the more typical FTD symptoms, including changes in social behavior and personality, as well as motor symptoms (Foster et al, 1997), are less predominant or not seen at all (Ikeuchi et al, 2011). Human iPSCs have the potential to differentiate into neurons, which have previously been difficult to obtain Using this model could thereby provide us with a deeper understanding of the molecular mechanism of the disease onset and progression

Results

Discussion

Conclusion