Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons
Abstract Background The prion-like spreading of Tau pathology is the leading cause of disease progression in various tauopathies. A critical step in propagating pathologic Tau in the brain is the transport from the extracellular environment and accumulation inside naïve neurons. Current research ind...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-12-01
|
| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13024-024-00786-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559130210304000 |
|---|---|
| author | Amir T. Marvian Tabea Strauss Qilin Tang Benjamin J. Tuck Sophie Keeling Daniel Rüdiger Negar Mirzazadeh Dizaji Hossein Mohammad-Beigi Brigitte Nuscher Pijush Chakraborty Duncan S. Sutherland William A. McEwan Thomas Köglsperger Stefan Zahler Markus Zweckstetter Stefan F. Lichtenthaler Wolfgang Wurst Sigrid Schwarz Günter Höglinger |
| author_facet | Amir T. Marvian Tabea Strauss Qilin Tang Benjamin J. Tuck Sophie Keeling Daniel Rüdiger Negar Mirzazadeh Dizaji Hossein Mohammad-Beigi Brigitte Nuscher Pijush Chakraborty Duncan S. Sutherland William A. McEwan Thomas Köglsperger Stefan Zahler Markus Zweckstetter Stefan F. Lichtenthaler Wolfgang Wurst Sigrid Schwarz Günter Höglinger |
| author_sort | Amir T. Marvian |
| collection | DOAJ |
| description | Abstract Background The prion-like spreading of Tau pathology is the leading cause of disease progression in various tauopathies. A critical step in propagating pathologic Tau in the brain is the transport from the extracellular environment and accumulation inside naïve neurons. Current research indicates that human neurons internalize both the physiological extracellular Tau (eTau) monomers and the pathological eTau aggregates. However, similarities or differences in neuronal transport mechanisms between Tau species remain elusive. Method Monomers, oligomers, and fibrils of recombinant 2N4R Tau were produced and characterized by biochemical and biophysical methods. A neuronal eTau uptake and accumulation assay was developed for human induced pluripotent stem cell-derived neurons (iPSCNs) and Lund human mesencephalic cells (LUHMES)-derived neurons. Mechanisms of uptake and cellular accumulation of eTau species were studied by using small molecule inhibitors of endocytic mechanisms and siRNAs targeting Tau uptake mediators. Results Extracellular Tau aggregates accumulated more than monomers in human neurons, mainly due to the higher efficiency of small fibrillar and soluble oligomeric aggregates in intraneuronal accumulation. A competition assay revealed a distinction in the neuronal accumulation between physiological eTau Monomers and pathology-relevant aggregates, suggesting differential transport mechanisms. Blocking heparan sulfate proteoglycans (HSPGs) with heparin only inhibited the accumulation of eTau aggregates, whereas monomers’ uptake remained unaltered. At the molecular level, the downregulation of genes involved in HSPG synthesis exclusively blocked neuronal accumulation of eTau aggregates but not monomers, suggesting its role in the transport of pathologic Tau. Moreover, the knockdown of LRP1, as a receptor of Tau, mainly reduced the accumulation of monomeric form, confirming its involvement in Tau’s physiological transport. Conclusion These data propose that despite the similarity in the cellular mechanism, the uptake and accumulation of eTau Monomers and aggregates in human neurons are regulated by different molecular mediators. Thus, they address the possibility of targeting the pathological spreading of Tau aggregates without disturbing the probable physiological or non-pathogenic transport of Tau Monomers. |
| format | Article |
| id | doaj-art-3e32f12e724542be8e8aee6d6af8d178 |
| institution | Kabale University |
| issn | 1750-1326 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj-art-3e32f12e724542be8e8aee6d6af8d1782025-01-05T12:46:02ZengBMCMolecular Neurodegeneration1750-13262024-12-0119112610.1186/s13024-024-00786-wDistinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neuronsAmir T. Marvian0Tabea Strauss1Qilin Tang2Benjamin J. Tuck3Sophie Keeling4Daniel Rüdiger5Negar Mirzazadeh Dizaji6Hossein Mohammad-Beigi7Brigitte Nuscher8Pijush Chakraborty9Duncan S. Sutherland10William A. McEwan11Thomas Köglsperger12Stefan Zahler13Markus Zweckstetter14Stefan F. Lichtenthaler15Wolfgang Wurst16Sigrid Schwarz17Günter Höglinger18Department of Neurology, School of Medicine, Klinikum rechts der Isar, Technical University of MunichGerman Center for Neurodegenerative Diseases (LMU)German Center for Neurodegenerative Diseases (LMU)UK Dementia Research Institute at the University of CambridgeUK Dementia Research Institute at the University of CambridgeDepartment of Pharmacy, Ludwig-Maximilians-University of MunichFaculty for Chemistry and Pharmacy, Ludwig-Maximilians-Universität MünchenDepartment of Biotechnology and Biomedicine, Technical University of DenmarkDivision of Metabolic Biochemistry, Biomedical Center (BMC), Ludwig-Maximilians-Universität MünchenDepartment for NMR-based Structural Biology, Max Planck Institute for Multidisciplinary SciencesInterdisciplinary Nanoscience Centre (iNANO), Aarhus UniversityUK Dementia Research Institute at the University of CambridgeDepartment of Neurology, University Hospital, Ludwig-Maximilians-Universität (LMU)Department of Pharmacy, Ludwig-Maximilians-University of MunichDepartment for NMR-based Structural Biology, Max Planck Institute for Multidisciplinary SciencesGerman Center for Neurodegenerative Diseases (LMU)German Center for Neurodegenerative Diseases (LMU)German Center for Neurodegenerative Diseases (LMU)German Center for Neurodegenerative Diseases (LMU)Abstract Background The prion-like spreading of Tau pathology is the leading cause of disease progression in various tauopathies. A critical step in propagating pathologic Tau in the brain is the transport from the extracellular environment and accumulation inside naïve neurons. Current research indicates that human neurons internalize both the physiological extracellular Tau (eTau) monomers and the pathological eTau aggregates. However, similarities or differences in neuronal transport mechanisms between Tau species remain elusive. Method Monomers, oligomers, and fibrils of recombinant 2N4R Tau were produced and characterized by biochemical and biophysical methods. A neuronal eTau uptake and accumulation assay was developed for human induced pluripotent stem cell-derived neurons (iPSCNs) and Lund human mesencephalic cells (LUHMES)-derived neurons. Mechanisms of uptake and cellular accumulation of eTau species were studied by using small molecule inhibitors of endocytic mechanisms and siRNAs targeting Tau uptake mediators. Results Extracellular Tau aggregates accumulated more than monomers in human neurons, mainly due to the higher efficiency of small fibrillar and soluble oligomeric aggregates in intraneuronal accumulation. A competition assay revealed a distinction in the neuronal accumulation between physiological eTau Monomers and pathology-relevant aggregates, suggesting differential transport mechanisms. Blocking heparan sulfate proteoglycans (HSPGs) with heparin only inhibited the accumulation of eTau aggregates, whereas monomers’ uptake remained unaltered. At the molecular level, the downregulation of genes involved in HSPG synthesis exclusively blocked neuronal accumulation of eTau aggregates but not monomers, suggesting its role in the transport of pathologic Tau. Moreover, the knockdown of LRP1, as a receptor of Tau, mainly reduced the accumulation of monomeric form, confirming its involvement in Tau’s physiological transport. Conclusion These data propose that despite the similarity in the cellular mechanism, the uptake and accumulation of eTau Monomers and aggregates in human neurons are regulated by different molecular mediators. Thus, they address the possibility of targeting the pathological spreading of Tau aggregates without disturbing the probable physiological or non-pathogenic transport of Tau Monomers.https://doi.org/10.1186/s13024-024-00786-wNeurodegenerationCell-to-cell spreadingExtracellular TauUptakeHSPGsLRP1 |
| spellingShingle | Amir T. Marvian Tabea Strauss Qilin Tang Benjamin J. Tuck Sophie Keeling Daniel Rüdiger Negar Mirzazadeh Dizaji Hossein Mohammad-Beigi Brigitte Nuscher Pijush Chakraborty Duncan S. Sutherland William A. McEwan Thomas Köglsperger Stefan Zahler Markus Zweckstetter Stefan F. Lichtenthaler Wolfgang Wurst Sigrid Schwarz Günter Höglinger Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons Molecular Neurodegeneration Neurodegeneration Cell-to-cell spreading Extracellular Tau Uptake HSPGs LRP1 |
| title | Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons |
| title_full | Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons |
| title_fullStr | Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons |
| title_full_unstemmed | Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons |
| title_short | Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons |
| title_sort | distinct regulation of tau monomer and aggregate uptake and intracellular accumulation in human neurons |
| topic | Neurodegeneration Cell-to-cell spreading Extracellular Tau Uptake HSPGs LRP1 |
| url | https://doi.org/10.1186/s13024-024-00786-w |
| work_keys_str_mv | AT amirtmarvian distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT tabeastrauss distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT qilintang distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT benjaminjtuck distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT sophiekeeling distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT danielrudiger distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT negarmirzazadehdizaji distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT hosseinmohammadbeigi distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT brigittenuscher distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT pijushchakraborty distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT duncanssutherland distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT williamamcewan distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT thomaskoglsperger distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT stefanzahler distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT markuszweckstetter distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT stefanflichtenthaler distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT wolfgangwurst distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT sigridschwarz distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons AT gunterhoglinger distinctregulationoftaumonomerandaggregateuptakeandintracellularaccumulationinhumanneurons |