Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations.

Tauopathies, such as Alzheimer's disease, some cases of frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy, are characterized by aggregates of the microtubule-associated protein tau, which are linked to neuronal death and disease development and can be caused by mutations in the MAPT gene. Six tau isoforms are present in the adult human brain and they differ by the presence of 3(3R) or 4(4R) C-terminal repeats. Only the shortest 3R isoform is present in foetal brain. MAPT mutations found in human disease affect tau binding to microtubules or the 3R:4R isoform ratio by altering exon 10 splicing. We have differentiated neurons from induced pluripotent stem cells derived from fibroblasts of controls and patients with N279K and P301L MAPT mutations. Induced pluripotent stem cell-derived neurons recapitulate developmental tau expression, showing the adult brain tau isoforms after several months in culture. Both N279K and P301L neurons exhibit earlier electrophysiological maturation and altered mitochondrial transport compared to controls. Specifically, the N279K neurons show abnormally premature developmental 4R tau expression, including changes in the 3R:4R isoform ratio and AT100-hyperphosphorylated tau aggregates, while P301L neurons are characterized by contorted processes with varicosity-like structures, some containing both alpha-synuclein and 4R tau. The previously unreported faster maturation of MAPT mutant human neurons, the developmental expression of 4R tau and the morphological alterations may contribute to disease development.This work was supported by CurePSP, The Cambridge Newton Trust, The William Scholl Foundation and the NIHR Cambridge Biomedical Research Centre (BRC). The contribution of the NC3Rs CRACK IT- Alzheimer’s Research UK is also acknowledged. S.A. holds a BBSRC studentship. A.G.-R. holds a Michael Foster Studentship. O.P. acknowledges BBSRC support. L.V. is supported by the ERC starting grant relieve-IMDs. S.O. and T.L. acknowledge support by the Irish Institute of Clinical Neuroscience. R.T.K. is supported by the Welcome Trust grant 091543/Z/10/Z and D.G. and M.dC.V.-H. are supported by Wellcome Trust grant #098051.This is the final version. It was first published by OUP at http://dx.doi.org/10.1093/brain/awv22