Journal article
C-Terminally Truncated Forms of Tau, But Not Full-Length Tau or Its C-Terminal Fragments, Are Released from Neurons Independently of Cell Death
The Journal of neuroscience, Vol.35(30), pp.10851-10865
07/29/2015
DOI: 10.1523/JNEUROSCI.0387-15.2015
PMCID: PMC6605107
PMID: 26224867
Abstract
Recent evidence suggests that tau aggregation may spread via extracellular release and subsequent uptake by synaptically connected neurons, but little is known about the processes by which tau is released or the molecular forms of extracellular tau. To gain insight into the nature of extracellular tau, we used highly sensitive ELISAs, which, when used in tandem, are capable of differentiating between full-length (FL) tau, mid-region-bearing fragments, and C-terminal (CT) fragments. We applied these assays to the systematic study of the conditioned media of N2a cells, induced pluripotent stem cell-derived human cortical neurons, and primary rat cortical neurons, each of which was carefully assessed for viability. In all three neuronal models, the bulk of extracellular tau was free-floating and unaggregated and <0.2% was encapsulated in exosomes. Although most intracellular tau was FL, the majority of extracellular tau was CT truncated and appeared to be released both actively by living neurons and passively by dead cells. In contrast, only a small amount of extracellular tau was aggregation-competent tau (i.e., contained the microtubule-binding regions) and this material appears to be released solely due to a low level of cell death that occurs in all cell culture systems. Importantly, amyloid β-protein (Aβ)-induced neuronal compromise significantly increased the quantity of all forms of extracellular tau, but the presence of Aβ before detectable cell compromise did not increase extracellular tau. Collectively, these results suggest that factors that induce neuronal death are likely to be necessary to initiate the extracellular spread of tau aggregation.
Recent studies suggest that the transfer of tau between neurons underlies the characteristic spatiotemporal progression of neurofibrillary pathology. We searched for tau in the conditioned medium of N2a cells, induced pluripotent stem cell-derived human cortical neurons, and primary rat cortical neurons and analyzed the material present using four different tau ELISAs. We demonstrate that the majority of tau released from healthy neurons is C-terminally truncated and lacks the microtubule-binding region (MTBR) thought necessary for self-aggregation. A small amount of MTBR-containing tau is present outside of cells, but this appears to be solely due to cell death. Therefore, if propagation of tau aggregation is mediated by extracellular tau, our findings suggest that neuronal compromise is required to facilitate this process.
Details
- Title: Subtitle
- C-Terminally Truncated Forms of Tau, But Not Full-Length Tau or Its C-Terminal Fragments, Are Released from Neurons Independently of Cell Death
- Creators
- Daniel Kanmert - Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115Adam Cantlon - Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, School of Bimolecular and Biomedical Science, University College Dublin, Dublin 4, Republic of Ireland, andChristina R Muratore - Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115Ming Jin - Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115Tiernan T O'Malley - Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115Gloria Lee - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Tracy L Young-Pearse - Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115Dennis J Selkoe - Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115Dominic M Walsh - Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, dwalsh3@partners.org
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.35(30), pp.10851-10865
- Publisher
- United States
- DOI
- 10.1523/JNEUROSCI.0387-15.2015
- PMID
- 26224867
- PMCID
- PMC6605107
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Grant note
- R01 AG017753 / NIA NIH HHS R01 AG006173 / NIA NIH HHS
- Language
- English
- Date published
- 07/29/2015
- Academic Unit
- Iowa Neuroscience Institute; Immunology; Internal Medicine
- Record Identifier
- 9984065382602771
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