@article{19b2dae6711f45d9b417b394367fd605,
title = "Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons",
abstract = "Tau is a microtubule-binding protein expressed in neurons, and the equal ratios between 4-repeat (4R) and 3-repeat (3R) isoforms are maintained in normal adult brain function. Dysregulation of 3R:4R ratio causes tauopathy, and human neurons that recapitulate tau isoforms in health and disease will provide a platform for elucidating pathogenic processes involving tau pathology. We carried out extensive characterizations of tau isoforms expressed in human neurons derived by microRNA-induced neuronal reprogramming of adult fibroblasts. Transcript and protein analyses showed that miR neurons expressed all six isoforms with the 3R:4R isoform ratio equivalent to that detected in human adult brains. Also, miR neurons derived from familial tauopathy patients with a 3R:4R ratio altering mutation showed increased 4R tau and the formation of insoluble tau with seeding activity. Our results collectively demonstrate the utility of miRNA-induced neuronal reprogramming to recapitulate endogenous tau regulation comparable with the adult brain in health and disease.",
keywords = "4R tau, adult human neurons, insoluble tau, microRNA-induced neurons, neuronal reprogramming, tau isoform ratio, tau isoforms, tau seeding, tauopathy",
author = "Capano, {Lucia S.} and Chihiro Sato and Elena Ficulle and Anan Yu and Kanta Horie and Kwon, {Ji Sun} and Burbach, {Kyle F.} and Barth{\'e}lemy, {Nicolas R.} and Fox, {Susan G.} and Karch, {Celeste M.} and Bateman, {Randall J.} and Henry Houlden and Morimoto, {Richard I.} and Holtzman, {David M.} and Duff, {Karen E.} and Yoo, {Andrew S.}",
note = "Funding Information: The authors would like to thank Edward D. Huey and Barbara Corneo (Columbia University) for providing one IVS10+16 fibroblast line, the Genome Technology Access Center and the fund from the Institute of Clinical and Translational Sciences (ICTS) (UL1TR002345) for their assistance in generating transcriptome dataset and iPSC lines, Mariana Beltcheva for iPSC-to-neuron differentiation, Kuo-Chan Weng for NPC expansion, Kitra Cates and Dr. Seongwon Lee for qPCR primers, Dr. Selina Wray for control and IVS10+16 iPSC-N lysate, Dr. Victoria Church for human brain miRNA, and Dr. Chloe He and Faris Shaikh for assisting with IP/MS experiments. This work was supported the following grants and awards: MCB training grant (T32 GM007067) (L.S.C.); ICTS JIT (JIT659H) (L.S.C. and A.S.Y.); Farrell Family Fund for Alzheimer's Disease (A.S.Y, C.M.K. and D.M.H.); Cure Alzheimer's Fund (A.S.Y.); NIH/NIA RF1AG056296 (A.S.Y.); NIH/NINDS R01NS107488 (A.S.Y.); Mallinckrodt Scholar Award (A.S.Y.); NIH/NIA K01AG062796 (C.S.); SILQ Center (R.J.B.); NIH/NINDS R01 NS095773 (R.J.B.); NIH/NIA AG063521 (K.E.D. and E.F.); the UK DRI funds from DRI Ltd, from the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK (K.E.D. and E.F.); MRC and Wellcome Trust (H.H.); NIH R56 NS110890 (C.M.K.); and Rainwater Charitable Organization (C.M.K.). ADRC Resources provided by Washington University Neuropathology core were supported by Healthy Aging and Senile Dementia (P01 AG03991), Alzheimer's Disease Research Center (P30 AG066444), Healthy Aging and Senile Dementia (P01 AG03991), Alzheimer Disease Research Center (P50 AG05691), and the Adult Children Study (P01 AG026276). Conceptualization, A.S.Y. D.M.H. K.E.D. and L.S.C.; methodology, A.S.Y. and L.S.C.; investigation, L.S.C. C.S. E.F. A.Y. K.H. J.-S.K. K.F.B. N.R.B. and S.G.F.; validation, A.S.Y. and S.G.F.; formal analysis, L.S.C.; writing – original draft, L.S.C. and A.S.Y.; writing – review and editing, all authors; supervision: R.J.B. R.I.M. K.E.D. and A.S.Y. D.M.H. is an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M.H. cofounded and is on the scientific advisory board of C2N Diagnostics. C2N Diagnostics has licensed certain anti-tau antibodies to AbbVie for therapeutic development. D.M.H. is on the scientific advisory board of Denali, Genentech (South San Francisco, CA, USA), and Cajal Neurosciences and consults for Genentech, Takeda, Casma, and Eli Lilly. A.S.Y. consults for Roche. K.H. is an EISAI-sponsored visiting researcher at Washington University and has received salary from Eisai. K.E.D. is a board member and advisor for Ceracuity LLC. All other authors declare no competing interests. Funding Information: The authors would like to thank Edward D. Huey and Barbara Corneo (Columbia University) for providing one IVS10+16 fibroblast line, the Genome Technology Access Center and the fund from the Institute of Clinical and Translational Sciences (ICTS) ( UL1TR002345 ) for their assistance in generating transcriptome dataset and iPSC lines, Mariana Beltcheva for iPSC-to-neuron differentiation, Kuo-Chan Weng for NPC expansion, Kitra Cates and Dr. Seongwon Lee for qPCR primers, Dr. Selina Wray for control and IVS10+16 iPSC-N lysate, Dr. Victoria Church for human brain miRNA, and Dr. Chloe He and Faris Shaikh for assisting with IP/MS experiments. This work was supported the following grants and awards: MCB training grant ( T32 GM007067 ) (L.S.C.); ICTS JIT ( JIT659H ) (L.S.C. and A.S.Y.); Farrell Family Fund for Alzheimer{\textquoteright}s Disease (A.S.Y, C.M.K., and D.M.H.); Cure Alzheimer{\textquoteright}s Fund (A.S.Y.); NIH/NIA RF1AG056296 (A.S.Y.); NIH/NINDS R01NS107488 (A.S.Y.); Mallinckrodt Scholar Award (A.S.Y.); NIH/NIA K01AG062796 (C.S.); SILQ Center (R.J.B.); NIH/NINDS R01 NS095773 (R.J.B.); NIH/NIA AG063521 (K.E.D. and E.F.); the UK DRI funds from DRI Ltd , from the UK Medical Research Council , Alzheimer{\textquoteright}s Society , and Alzheimer{\textquoteright}s Research UK (K.E.D. and E.F.); MRC and Wellcome Trust (H.H.); NIH R56 NS110890 (C.M.K.); and Rainwater Charitable Organization (C.M.K.). ADRC Resources provided by Washington University Neuropathology core were supported by Healthy Aging and Senile Dementia ( P01 AG03991 ), Alzheimer{\textquoteright}s Disease Research Center ( P30 AG066444 ), Healthy Aging and Senile Dementia ( P01 AG03991 ), Alzheimer Disease Research Center ( P50 AG05691 ), and the Adult Children Study ( P01 AG026276 ). Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = jun,
day = "2",
doi = "10.1016/j.stem.2022.04.018",
language = "English",
volume = "29",
pages = "918--932.e8",
journal = "Cell Stem Cell",
issn = "1934-5909",
number = "6",
}