ZFN engineered hiPSC with the FTDP-17 associated MAPT IVS10+16 mutation w/wo additional P301S mutation

The development of an effective therapy against tauopathies like Alzheimers disease (AD) and frontotemporal dementia (FTD) remains challenging, partly due to limited access to fresh brain tissue, the lack of translational in vitro disease models and the fact that underlying molecular pathways remain to be deciphered. Several genes play an important role in the pathogenesis of AD and FTD, one of them being the MAPT gene encoding the microtubule-associated protein tau. Over the past few years, it has been shown that induced pluripotent stem cells (iPSC) can be used to model various human disorders and can serve as translational in vitro tools. Therefore, we generated iPSC harboring the pathogenic FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) associated mutations IVS10+16 with and without P301S in MAPT using Zinc Finger Nuclease technology. Whole transcriptome analysis of MAPT IVS10+16 neurons reveals neuronal subtype differences, reduced neural progenitor proliferation potential and aberrant WNT signaling. Notably, all phenotypes were recapitulated using patient-derived neurons. Finally, an additional P301S mutation causes an increased calcium bursting frequency, reduced lysosomal acidity and tau oligomerization.

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Verheyen A, Diels A, Reumers J, Van Hoorde K, Van den Wyngaert I, van Outryve d'Ydewalle C, De Bondt A, Kuijlaars J, De Muynck L, De Hoogt R, Bretteville A, Jaensch S, Buist A, Cabrera-Socorro A, Wray S, Ebneth A, Roevens P, Royaux I, Peeters PJ