TY  - JOUR
AU  - Tayaranian Marvian, Amir
AU  - Strauß, Tabea
AU  - Tang, Qilin
AU  - Tuck, Benjamin J
AU  - Keeling, Sophie
AU  - Rüdiger, Daniel
AU  - Mirzazadeh Dizaji, Negar
AU  - Mohammad-Beigi, Hossein
AU  - Nuscher, Brigitte
AU  - Chakraborty, Pijush
AU  - Sutherland, Duncan S
AU  - McEwan, William A
AU  - Köglsperger, Thomas
AU  - Zahler, Stefan
AU  - Zweckstetter, Markus
AU  - Lichtenthaler, Stefan F
AU  - Wurst, Wolfgang
AU  - Schwarz, Sigrid
AU  - Höglinger, Günter
TI  - Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons.
JO  - Molecular neurodegeneration
VL  - 19
IS  - 1
SN  - 1750-1326
CY  - London
PB  - Biomed Central
M1  - DZNE-2025-00006
SP  - 100
PY  - 2024
AB  - 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.
KW  - Humans
KW  - tau Proteins: metabolism
KW  - Neurons: metabolism
KW  - Tauopathies: metabolism
KW  - Tauopathies: pathology
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Protein Aggregates: physiology
KW  - Cell-to-cell spreading (Other)
KW  - Extracellular Tau (Other)
KW  - HSPGs (Other)
KW  - LRP1 (Other)
KW  - Neurodegeneration (Other)
KW  - Uptake (Other)
KW  - VPS35 (Other)
KW  - tau Proteins (NLM Chemicals)
KW  - Protein Aggregates (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39736627
C2  - pmc:PMC11686972
DO  - DOI:10.1186/s13024-024-00786-w
UR  - https://pub.dzne.de/record/274025
ER  -