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@ARTICLE{TayaranianMarvian:274025,
      author       = {Tayaranian Marvian, Amir and Strauß, Tabea and Tang, Qilin
                      and Tuck, Benjamin J and Keeling, Sophie and Rüdiger,
                      Daniel and Mirzazadeh Dizaji, Negar and Mohammad-Beigi,
                      Hossein and Nuscher, Brigitte and Chakraborty, Pijush and
                      Sutherland, Duncan S and McEwan, William A and Köglsperger,
                      Thomas and Zahler, Stefan and Zweckstetter, Markus and
                      Lichtenthaler, Stefan F and Wurst, Wolfgang and Schwarz,
                      Sigrid and Höglinger, Günter},
      title        = {{D}istinct regulation of {T}au {M}onomer and aggregate
                      uptake and intracellular accumulation in human neurons.},
      journal      = {Molecular neurodegeneration},
      volume       = {19},
      number       = {1},
      issn         = {1750-1326},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2025-00006},
      pages        = {100},
      year         = {2024},
      abstract     = {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.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.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.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.},
      keywords     = {Humans / tau Proteins: metabolism / Neurons: metabolism /
                      Tauopathies: metabolism / Tauopathies: pathology / Induced
                      Pluripotent Stem Cells: metabolism / Protein Aggregates:
                      physiology / Cell-to-cell spreading (Other) / Extracellular
                      Tau (Other) / HSPGs (Other) / LRP1 (Other) /
                      Neurodegeneration (Other) / Uptake (Other) / VPS35 (Other) /
                      tau Proteins (NLM Chemicals) / Protein Aggregates (NLM
                      Chemicals) / MAPT protein, human (NLM Chemicals)},
      cin          = {Clinical Research (Munich) / AG Simons / AG Höglinger / AG
                      Zweckstetter / AG Lichtenthaler / AG Wurst},
      ddc          = {570},
      cid          = {I:(DE-2719)1111015 / I:(DE-2719)1110008 /
                      I:(DE-2719)1110002 / I:(DE-2719)1410001 / I:(DE-2719)1110006
                      / I:(DE-2719)1140001},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 351 -
                      Brain Function (POF4-351) / 352 - Disease Mechanisms
                      (POF4-352)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-351 /
                      G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39736627},
      pmc          = {pmc:PMC11686972},
      doi          = {10.1186/s13024-024-00786-w},
      url          = {https://pub.dzne.de/record/274025},
}