@article{3783bf79393b407fb03b51b3157cfd84,
title = "Tau Kinetics in Neurons and the Human Central Nervous System",
abstract = "We developed stable isotope labeling and mass spectrometry approaches to measure the kinetics of multiple isoforms and fragments of tau in the human central nervous system (CNS) and in human induced pluripotent stem cell (iPSC)-derived neurons. Newly synthesized tau is truncated and released from human neurons in 3 days. Although most tau proteins have similar turnover, 4R tau isoforms and phosphorylated forms of tau exhibit faster turnover rates, suggesting unique processing of these forms that may have independent biological activities. The half-life of tau in control human iPSC-derived neurons is 6.74 ± 0.45 days and in human CNS is 23 ± 6.4 days. In cognitively normal and Alzheimer's disease participants, the production rate of tau positively correlates with the amount of amyloid plaques, indicating a biological link between amyloid plaques and tau physiology. Sato et al. show that stable isotope labeling kinetics enable measurement of tau in the CNS and in iPSC-derived neurons. Specific forms of tau are uniquely processed in neurons and tau production rates correlate with amyloid accumulation in human subjects.",
keywords = "Alzheimer's disease, PET, SILK, amyloid, human, induced pluripotent stem cell, isoform, phosphorylation, positron emission tomography, production rate, stable isotope labeling kinetics, tau",
author = "Chihiro Sato and Barth{\'e}lemy, {Nicolas R.} and Mawuenyega, {Kwasi G.} and Patterson, {Bruce W.} and Gordon, {Brian A.} and Jennifer Jockel-Balsarotti and Melissa Sullivan and Crisp, {Matthew J.} and Tom Kasten and Kirmess, {Kristopher M.} and Kanaan, {Nicholas M.} and Yarasheski, {Kevin E.} and Alaina Baker-Nigh and Benzinger, {Tammie L.S.} and Miller, {Timothy M.} and Karch, {Celeste M.} and Bateman, {Randall J.}",
note = "Funding Information: This work was supported by the BrightFocus Foundation ( A2014384S ) (R.J.B.), Tau SILK Consortium (AbbVie, Biogen, and Eli Lily; R.J.B.), NIH ( R01NS095773 ) (R.J.B.), MetLife Foundation (R.J.B.), Knight ADRC pilot grant P50AG05681 (C.S.), Coins for Alzheimer{\textquoteright}s Research Trust (CART) grant (C.S.), Barnes-Jewish Hospital Foundation pilot grant UL1TR002345 (C.S.), the 41st Kanae Foundation for the Promotion of Science Fellowship (C.S.), McDonnell Science Grant for Neuroscience (C.M.K. and C.S.), NIH ( R01NS078398 ) (T.M.M), ALS Association ( 2427 ) (T.M.M.), NIH ( K01 AG046374 ) (C.M.K.), NIH ( P30DK056341 ) (Washington University Nutrition Obesity Research Center; B.W.P.), DIAN-TU Pharma Consortium ( https://dian.wustl.edu/our-research/the-pharma-consortium/ ) (R.J.B. and C.M.K.), Barnes-Jewish Hospital Foundation (T.L.S.B.), NIH ( P01AG003991 ) (T.L.S.B), NIH ( UL1TR000448 ) (T.L.S.B.), NIH ( P30NS098577 ) (T.L.S.B.), NIH ( P01AG026276 ) (T.L.S.B.), NIH ( K01 AG053474 ) (B.A.G.), Tau Consortium (C.M.K., R.J.B., and T.M.M.), Alzheimer{\textquoteright}s Association Research Fellowship ( AARF-16-443265 ) (N.R.B.), and cores, resources, and effort provided by Washington University Knight Alzheimer{\textquoteright}s Research Center ( NIH P50AG005681 ), Biomedical Mass Spectrometry Research Facility ( NIH P41GM103422 ), Diabetes Research Center ( NIH P30DK020579 ), and the Nutrition Obesity Research Center ( NIH P30DK056341 ). This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine. We thank the participants and their families for their contributions to this study, including Andrew Jackson Bateman, who was a consummate believer in the human mind and spirit. We thank ADRC clinical core and Dr. John Morris for supporting our study; Dr. David Holtzman and Ms. Hong Jiang for HJ antibodies; Dr. Lester Binder for the Tau12, Tau13, and Tau7 antibodies; Dr. Sungsu Kim for HEK cells and discussion; Ms. Rita Martinez for iPSC-derived neuron culture; Cheryl Frankfater and Freida Custodio for assistance with GC-MS analyses; Ms. Melody Li, Wendy Sigurdson, and Tamara Donahue for assistance with recruitment; Dr. Nigel Cairns for discussion on brain cutting; Ms. Erin Franklin for assistance with sample request; Dr. Gregg Day for collecting CSF from normal controls; Mr. Paul Moiseyev for preparing brain lysate; Drs. Robert Swarm and Lesly Rao for performing LPs; and members of the Bateman lab for discussion, in particular Dr. Katrina Paumier and Ms. Terry Hicks for assistance in editing the manuscript. Funding Information: This work was supported by the BrightFocus Foundation (A2014384S) (R.J.B.), Tau SILK Consortium (AbbVie, Biogen, and Eli Lily; R.J.B.), NIH (R01NS095773) (R.J.B.), MetLife Foundation (R.J.B.), Knight ADRC pilot grant P50AG05681 (C.S.), Coins for Alzheimer's Research Trust (CART) grant (C.S.), Barnes-Jewish Hospital Foundation pilot grant UL1TR002345 (C.S.), the 41st Kanae Foundation for the Promotion of Science Fellowship (C.S.), McDonnell Science Grant for Neuroscience (C.M.K. and C.S.), NIH (R01NS078398) (T.M.M), ALS Association (2427) (T.M.M.), NIH (K01 AG046374) (C.M.K.), NIH (P30DK056341) (Washington University Nutrition Obesity Research Center; B.W.P.), DIAN-TU Pharma Consortium (https://dian.wustl.edu/our-research/the-pharma-consortium/) (R.J.B. and C.M.K.), Barnes-Jewish Hospital Foundation (T.L.S.B.), NIH (P01AG003991) (T.L.S.B), NIH (UL1TR000448) (T.L.S.B.), NIH (P30NS098577) (T.L.S.B.), NIH (P01AG026276) (T.L.S.B.), NIH (K01 AG053474) (B.A.G.), Tau Consortium (C.M.K., R.J.B., and T.M.M.), Alzheimer's Association Research Fellowship (AARF-16-443265) (N.R.B.), and cores, resources, and effort provided by Washington University Knight Alzheimer's Research Center (NIH P50AG005681), Biomedical Mass Spectrometry Research Facility (NIH P41GM103422), Diabetes Research Center (NIH P30DK020579), and the Nutrition Obesity Research Center (NIH P30DK056341). This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine. We thank the participants and their families for their contributions to this study, including Andrew Jackson Bateman, who was a consummate believer in the human mind and spirit. We thank ADRC clinical core and Dr. John Morris for supporting our study; Dr. David Holtzman and Ms. Hong Jiang for HJ antibodies; Dr. Lester Binder for the Tau12, Tau13, and Tau7 antibodies; Dr. Sungsu Kim for HEK cells and discussion; Ms. Rita Martinez for iPSC-derived neuron culture; Cheryl Frankfater and Freida Custodio for assistance with GC-MS analyses; Ms. Melody Li, Wendy Sigurdson, and Tamara Donahue for assistance with recruitment; Dr. Nigel Cairns for discussion on brain cutting; Ms. Erin Franklin for assistance with sample request; Dr. Gregg Day for collecting CSF from normal controls; Mr. Paul Moiseyev for preparing brain lysate; Drs. Robert Swarm and Lesly Rao for performing LPs; and members of the Bateman lab for discussion, in particular Dr. Katrina Paumier and Ms. Terry Hicks for assistance in editing the manuscript. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = mar,
day = "21",
doi = "10.1016/j.neuron.2018.02.015",
language = "English",
volume = "97",
pages = "1284--1298.e7",
journal = "Neuron",
issn = "0896-6273",
number = "6",
}