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000274025 041__ $$aEnglish
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000274025 1001_ $$0P:(DE-2719)9000203$$aTayaranian Marvian, Amir$$b0$$eFirst author$$udzne
000274025 245__ $$aDistinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons.
000274025 260__ $$aLondon$$bBiomed Central$$c2024
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000274025 520__ $$aThe 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.
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000274025 650_7 $$2Other$$aCell-to-cell spreading
000274025 650_7 $$2Other$$aExtracellular Tau
000274025 650_7 $$2Other$$aHSPGs
000274025 650_7 $$2Other$$aLRP1
000274025 650_7 $$2Other$$aNeurodegeneration
000274025 650_7 $$2Other$$aUptake
000274025 650_7 $$2Other$$aVPS35
000274025 650_7 $$2NLM Chemicals$$atau Proteins
000274025 650_7 $$2NLM Chemicals$$aProtein Aggregates
000274025 650_7 $$2NLM Chemicals$$aMAPT protein, human
000274025 650_2 $$2MeSH$$aHumans
000274025 650_2 $$2MeSH$$atau Proteins: metabolism
000274025 650_2 $$2MeSH$$aNeurons: metabolism
000274025 650_2 $$2MeSH$$aTauopathies: metabolism
000274025 650_2 $$2MeSH$$aTauopathies: pathology
000274025 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000274025 650_2 $$2MeSH$$aProtein Aggregates: physiology
000274025 7001_ $$0P:(DE-2719)2811799$$aStrauß, Tabea$$b1
000274025 7001_ $$0P:(DE-2719)9001127$$aTang, Qilin$$b2$$udzne
000274025 7001_ $$aTuck, Benjamin J$$b3
000274025 7001_ $$aKeeling, Sophie$$b4
000274025 7001_ $$aRüdiger, Daniel$$b5
000274025 7001_ $$aMirzazadeh Dizaji, Negar$$b6
000274025 7001_ $$aMohammad-Beigi, Hossein$$b7
000274025 7001_ $$aNuscher, Brigitte$$b8
000274025 7001_ $$0P:(DE-2719)2812532$$aChakraborty, Pijush$$b9$$udzne
000274025 7001_ $$aSutherland, Duncan S$$b10
000274025 7001_ $$aMcEwan, William A$$b11
000274025 7001_ $$0P:(DE-2719)2810825$$aKöglsperger, Thomas$$b12$$udzne
000274025 7001_ $$aZahler, Stefan$$b13
000274025 7001_ $$0P:(DE-2719)2810591$$aZweckstetter, Markus$$b14$$udzne
000274025 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F$$b15$$udzne
000274025 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b16$$udzne
000274025 7001_ $$0P:(DE-2719)2812262$$aSchwarz, Sigrid$$b17$$udzne
000274025 7001_ $$0P:(DE-2719)2811373$$aHöglinger, Günter$$b18$$eLast author$$udzne
000274025 773__ $$0PERI:(DE-600)2244557-2$$a10.1186/s13024-024-00786-w$$gVol. 19, no. 1, p. 100$$n1$$p100$$tMolecular neurodegeneration$$v19$$x1750-1326$$y2024
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