PMID- 28610892 OWN - NLM STAT- MEDLINE DCOM- 20180515 LR - 20240216 IS - 1095-953X (Electronic) IS - 0969-9961 (Print) IS - 0969-9961 (Linking) VI - 106 DP - 2017 Oct TI - Novel human neuronal tau model exhibiting neurofibrillary tangles and transcellular propagation. PG - 222-234 LID - S0969-9961(17)30131-6 [pii] LID - 10.1016/j.nbd.2017.06.005 [doi] AB - Tauopathies are a class of neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy, which are associated with the pathological aggregation of tau protein into neurofibrillary tangles (NFT). Studies have characterized tau as a "prion-like" protein given its ability to form distinct, stable amyloid conformations capable of transcellular and multigenerational propagation in clonal fashion. It has been proposed that progression of tauopathy could be due to the prion-like propagation of tau, suggesting the possibility that end-stage pathologies, like NFT formation, may require an instigating event such as tau seeding. To investigate this, we applied a novel human induced pluripotent stem cell (hiPSC) system we have developed to serve as a human neuronal model. We introduced the tau repeat domain (tau-RD) with P301L and V337M (tau-RD-LM) mutations into hiPSC-derived neurons and observed expression of tau-RD at levels similar to total tau in postmortem AD brains. Tau aggregation occurred without the addition of recombinant tau fibrils. The conditioned media from tau-RD cultures contained tau-RD seeds, which were capable of inducing aggregate formation in homotypic mode in non-transduced recipient neuronal cultures. The resultant NFTs were thioflavin-positive, silver stain-positive, and assumed fibrillary appearance on transmission electron microscopy (TEM) with immunogold, which revealed paired helical filament 1 (PHF1)-positive NFTs, representing possible recruitment of endogenous tau in the aggregates. Functionally, expression of tau-RD caused neurotoxicity that manifested as axon retraction, synaptic density reduction, and enlargement of lysosomes. The results of our hiPSC study were reinforced by the observation that Tau-RD-LM is excreted in exosomes, which mediated the transfer of human tau to wild-type mouse neurons in vivo. Our hiPSC human neuronal system provides a model for further studies of tau aggregation and pathology as well as a means to study transcellular propagation and related neurodegenerative mechanisms. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Reilly, Patrick AU - Reilly P AD - Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States. FAU - Winston, Charisse N AU - Winston CN AD - Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States. FAU - Baron, Kelsey R AU - Baron KR AD - Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States. FAU - Trejo, Margarita AU - Trejo M AD - Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States; Department of Pathology, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States. FAU - Rockenstein, Edward M AU - Rockenstein EM AD - Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States. FAU - Akers, Johnny C AU - Akers JC AD - Department of Neurosurgery, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States. FAU - Kfoury, Najla AU - Kfoury N AD - Department of Neurology, Washington University, Saint Louis, MO 63110, United States. FAU - Diamond, Marc AU - Diamond M AD - Department of Neurology, Washington University, Saint Louis, MO 63110, United States. FAU - Masliah, Eliezer AU - Masliah E AD - Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States; Department of Pathology, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States. FAU - Rissman, Robert A AU - Rissman RA AD - Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States; Veterans Affairs San Diego Healthcare System, San Diego, CA, 92161 United States. FAU - Yuan, Shauna H AU - Yuan SH AD - Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States. Electronic address: shyuan@ucsd.edu. LA - eng GR - R21 AG051839/AG/NIA NIH HHS/United States GR - P50 AG005131/AG/NIA NIH HHS/United States GR - I01 BX003040/BX/BLRD VA/United States GR - R01 AG051848/AG/NIA NIH HHS/United States GR - T32 AG000216/AG/NIA NIH HHS/United States PT - Journal Article DEP - 20170610 PL - United States TA - Neurobiol Dis JT - Neurobiology of disease JID - 9500169 RN - 0 (Culture Media, Conditioned) RN - 0 (MAPT protein, human) RN - 0 (PSEN1 protein, human) RN - 0 (Presenilin-1) RN - 0 (tau Proteins) SB - IM MH - Animals MH - Brain/metabolism/pathology MH - Cells, Cultured MH - Culture Media, Conditioned MH - Disease Models, Animal MH - Exosomes/metabolism/transplantation MH - Female MH - Humans MH - Induced Pluripotent Stem Cells/*metabolism/pathology MH - Mice, Inbred C57BL MH - Mutation MH - Neurofibrillary Tangles/*metabolism/pathology MH - Neurons/metabolism/pathology MH - Presenilin-1/genetics/metabolism MH - Tauopathies/*metabolism/pathology MH - tau Proteins/*metabolism PMC - PMC5593133 MID - NIHMS893739 OTO - NOTNLM OT - Exosomes OT - Induced pluripotent stem cells OT - Neurofibrillary tangles OT - Propagation OT - Tau EDAT- 2017/06/15 06:00 MHDA- 2018/05/16 06:00 PMCR- 2018/10/01 CRDT- 2017/06/15 06:00 PHST- 2017/03/10 00:00 [received] PHST- 2017/05/18 00:00 [revised] PHST- 2017/06/09 00:00 [accepted] PHST- 2017/06/15 06:00 [pubmed] PHST- 2018/05/16 06:00 [medline] PHST- 2017/06/15 06:00 [entrez] PHST- 2018/10/01 00:00 [pmc-release] AID - S0969-9961(17)30131-6 [pii] AID - 10.1016/j.nbd.2017.06.005 [doi] PST - ppublish SO - Neurobiol Dis. 2017 Oct;106:222-234. doi: 10.1016/j.nbd.2017.06.005. Epub 2017 Jun 10.