Tau Kinetics in Neurons and the Human Central Nervous System

• Published in: Neuron (Cambridge, Mass.) Vol. 97; no. 6; pp. 1284 - 1298.e7
• Main Authors: Sato, Chihiro, Barthélemy, Nicolas R., Mawuenyega, Kwasi G., Patterson, Bruce W., Gordon, Brian A., Jockel-Balsarotti, Jennifer, Sullivan, Melissa, Crisp, Matthew J., Kasten, Tom, Kirmess, Kristopher M., Kanaan, Nicholas M., Yarasheski, Kevin E., Baker-Nigh, Alaina, Benzinger, Tammie L.S., Miller, Timothy M., Karch, Celeste M., Bateman, Randall J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.03.2018; Elsevier Limited
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amino Acid Sequence; amyloid; Biomarkers - cerebrospinal fluid; Brain; Brain - metabolism; Brain - pathology; Cell Line; Cells, Cultured; Central nervous system; Central Nervous System - metabolism; Central Nervous System - pathology; Dementia; Female; human; Humans; Immunoglobulins; induced pluripotent stem cell; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; isoform; Isoforms; Kinetics; Labeling; Male; Mass spectroscopy; Middle Aged; Neurons; Pathology; Peptides; PET; phosphorylation; Physiology; Pluripotency; positron emission tomography; production rate; Proteins; Senile plaques; SILK; stable isotope labeling kinetics; Stem cells; tau; Tau protein; tau Proteins - cerebrospinal fluid; tau Proteins - metabolism; SILK; amyloid; Alzheimer’s disease; induced pluripotent stem cell; stable isotope labeling kinetics; production rate; tau; positron emission tomography; phosphorylation; human; isoform; PET
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2018.02.015

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. [Display omitted] •Multiple forms of tau exist in the human brain, CSF, and iPSC-derived neurons•Newly synthesized tau is truncated and actively released by human neurons•Fibrillogenic forms of tau have shorter half-lives than non-fibrillogenic forms•Tau production rate positively correlates with amyloid plaque burden 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.