Hyperphosphorylation of tau incorrectly sorts tau into the somatodendritic compartment, which is linked to dysfunctional axonal transport , one of the earliest pathological features of tauopathies. tau (blocks soluble tau uptake including tau monomers/oligomers, but only reduce tau fibrils uptake[36] Open in a separate window The majority of extracellular tau consists of soluble oligomers and monomers, while a minority of tau species exist in truncated forms cleaved by various proinflammatory cytokines in AD brains [6]. The size and conformation of tau species determine the cellular mechanisms for extracellular tau uptake, which may not be restricted to one particular pathway [8,36]. For instance, smaller sized tau aggregates enter neurons in a dynamin-dependent endocytosis pathway that is impartial of actin polymerization [35]. For larger tau aggregates, actin-dependent macropinocytosis has been identified as the main pathway for internalization by neuronal cells [37]. However, the cellular entry pathways of monomeric tau are highly dependent on the specific conformation and isoform. A recent study exhibited that monomeric tau could enter human neurons via both the dynamin-dependent endocytosis process and through actin-dependent macropinocytosis, which could be regulated by HSPGs [35]. 3.1. The Effects of HSPGs around the Cellular Uptake of Tau Seeds HSPGs are highly expressed around the cell surface and have been identified as critical cell-surface endocytosis receptors for tau internalization in various studies. Most recent research has focused on understanding the conversation of heparan sulfate (HS) with tau protein at the structural level, which would provide a mechanistic understanding of how tau-HS conversation regulates tau internalization during the progression of tau pathologies. HS-tau interactions appear to be driven mainly by electrostatic forces between negatively charged sulfo groups on HS and positively charged lysines or arginines on tau protein [38]. Even though electrostatic interactions between tau and HS are relatively nonspecific, a few studies have also identified the importance of specific HS sulfation patterns around the tau-HS conversation. Prior works exhibited the crucial role of the 6-O-sulfation of HSPGs in the tau-HS conversation by performing an SPR competition assay [39]. Moreover, 6-O-desulfated heparin showed the weakest competitive effect on tau binding to heparin immobilized on a chip among a variety of HS derivatives tested, including N-desulfated and 2-O-desulfated HS derivatives. NMR mapping showed that HS derivatives bound the second repeat motif (R2) in tau. Consistently, a knockout of 6-O-sulfotransferase also significantly reduced tau uptake by HEK293 cells [40]. Reduced intracellular tau uptake and tau cell surface binding in a 3-O-sulfotransferase knockout cell line compared with the wild-type cells suggest that tau protein is capable of recognizing the less common 3-O-sulfation site of HS [41]. The importance of sulfation was further validated in competition assays performed by Zhao and coworkers3-O-sulfated low molecular weight HS (LMWHS) oligosaccharides had higher inhibitory effects around the tau-HS conversation compared with those without sulfation in an SPR competition assay, further validating the specific role of 3-O-sulfation in tau-heparin interactions. Furthermore, 3-O-sulfation is usually rare and minor sulfation is found on HS chains, which is likely not responsible for any charge effects in HS chains. KN-62 More likely, HS interacts with tau via a specific 3-O-sulfation of HS recognized by both the PRR2 and R2 regions of tau instead of nonspecific electrostatic interactions. The tau-heparin conversation has also been found to be chain size-dependent due to enhanced electrostatic interactions [40]. Knockouts of extension enzymes of the HSPG biosynthetic pathway, such as extension enzymes exostosin 1 (with a P301S mutation and display a series of pathological features of tauopathies, such as gliosis, synaptic loss, tangles, and neuronal loss over their lifetimes. Adapted from [51,52]. Note that in this model, no plaques were found; LTP, long-term potentiation; LTD, long-term depressive disorder. (B) Both microgliosis and astrogliosis are involved in the progression of tauopathies and abnormal neuronal activities, as indicated by phenotypic characterization of human tau pathology models [53]. Copyright ? 2021, John Wiley and Sons. As described in detail in the following sections, the.Additionally, ApoE4 cerebral organoids exhibited an elevated level of phosphorylated tau (p-S202/T205) compared with ApoE3 organoids. tau fibrils uptake[36] Open in a separate window The majority of extracellular tau consists of soluble oligomers and monomers, while a minority of tau species exist in truncated forms cleaved by various proinflammatory cytokines in AD brains [6]. The size and conformation of tau species determine the cellular mechanisms for extracellular tau uptake, which may not be restricted to one particular pathway KN-62 [8,36]. For instance, smaller sized tau aggregates enter neurons in a dynamin-dependent endocytosis pathway that is independent of actin polymerization [35]. For larger tau aggregates, actin-dependent macropinocytosis has been identified as the main pathway for internalization by neuronal cells [37]. However, the cellular entry pathways of monomeric tau are highly dependent on the specific conformation and isoform. A recent study demonstrated that monomeric tau could enter human neurons via both the dynamin-dependent endocytosis process and through actin-dependent macropinocytosis, which could be regulated by HSPGs [35]. 3.1. The Effects of HSPGs on the Cellular Uptake of Tau Seeds HSPGs are highly expressed on the cell surface and have been identified as critical cell-surface endocytosis receptors for tau internalization in various studies. Most recent research has focused on understanding the interaction of heparan sulfate (HS) with tau protein at the structural level, which would provide a mechanistic understanding of how tau-HS interaction regulates tau internalization during the progression of tau pathologies. HS-tau interactions appear to be driven mainly by electrostatic forces between negatively charged sulfo groups on HS and positively charged lysines or arginines on tau protein [38]. Even though electrostatic interactions between tau and HS are relatively nonspecific, a few studies have also identified the importance of specific HS sulfation patterns on the tau-HS interaction. Prior works demonstrated the crucial role of the 6-O-sulfation of HSPGs in the tau-HS interaction by performing an SPR competition assay [39]. Moreover, 6-O-desulfated heparin showed the weakest competitive effect on tau binding to heparin immobilized on a chip among a variety of HS derivatives tested, including N-desulfated and 2-O-desulfated HS derivatives. NMR mapping showed that HS derivatives bound the second repeat motif (R2) in tau. Consistently, a knockout of 6-O-sulfotransferase also significantly reduced tau uptake by HEK293 cells [40]. Reduced intracellular tau uptake and tau cell surface binding in a 3-O-sulfotransferase knockout cell line compared with the wild-type cells suggest that tau protein is capable of recognizing the less common 3-O-sulfation site of HS [41]. The importance of sulfation was further validated in competition assays performed by Zhao and coworkers3-O-sulfated low molecular weight HS (LMWHS) oligosaccharides had higher inhibitory effects on the tau-HS interaction compared with those without sulfation in an SPR competition assay, further validating the specific role of 3-O-sulfation in tau-heparin interactions. Furthermore, 3-O-sulfation is rare and minor sulfation is found on HS chains, which is likely not responsible for any charge effects in HS chains. More likely, HS interacts with tau via a specific 3-O-sulfation of HS recognized by both the PRR2 and R2 regions of tau instead of nonspecific electrostatic interactions. The tau-heparin interaction has also been found to be chain size-dependent due to enhanced electrostatic interactions [40]. Knockouts of extension enzymes of the HSPG biosynthetic pathway, such as extension enzymes exostosin 1 (with a P301S mutation and display a series of pathological features of tauopathies, such as gliosis, synaptic loss, tangles, and neuronal loss over their lifetimes. Adapted from [51,52]. Note that in this model, no plaques were found; LTP, long-term potentiation; LTD, long-term depression. (B) Both microgliosis and astrogliosis are involved in the progression of tauopathies and abnormal neuronal activities, as indicated by phenotypic characterization of human tau pathology models [53]. Copyright ? 2021, John Wiley and Sons. As described in detail in the following sections, the development of tau-related pathologies has been postulated.While neuroprotective effects of glial cellsincluding phagocytotic microglial and astroglial phenotypeshave been observed at the early stage of neurodegeneration, dysfunctional neuronal-glial cellular communication results in a series of further pathological consequences as the disease progresses, including abnormal axonal transport, synaptic degeneration, and neuronal loss, accompanied by a pro-inflammatory microenvironment. cellular communication results in a series of further pathological consequences as the disease progresses, including abnormal axonal transport, synaptic degeneration, and neuronal loss, accompanied by a pro-inflammatory microenvironment. Additionally, the discovery of microtubule-associated protein tau (blocks soluble tau uptake including tau monomers/oligomers, but only reduce tau fibrils uptake[36] Open in a separate window The majority of extracellular tau consists of soluble oligomers and monomers, while a minority of tau species exist in truncated forms cleaved by numerous proinflammatory cytokines in AD brains [6]. The size and conformation of tau varieties determine the cellular mechanisms for extracellular tau uptake, which may not become restricted to one particular pathway [8,36]. For instance, smaller sized tau aggregates enter neurons inside a dynamin-dependent endocytosis pathway that is self-employed of actin polymerization [35]. For larger tau aggregates, actin-dependent macropinocytosis has been identified as the main pathway for internalization by neuronal cells [37]. However, the cellular access pathways of monomeric tau are highly dependent on the specific conformation and isoform. A recent study shown that monomeric tau could enter human being neurons via both the dynamin-dependent endocytosis process and through actin-dependent macropinocytosis, which could become controlled by HSPGs [35]. 3.1. The Effects of HSPGs within the Cellular Uptake of Tau Seeds HSPGs are highly expressed within the cell surface and have been identified as crucial cell-surface endocytosis receptors for tau KN-62 internalization in various studies. Most recent research has focused on understanding the connection of heparan sulfate (HS) with tau protein in the structural level, which would provide a mechanistic understanding of how tau-HS connection regulates tau internalization during the progression of tau pathologies. HS-tau relationships look like driven primarily by electrostatic causes between negatively charged sulfo organizations on HS and positively charged lysines or arginines on tau protein [38]. Even though electrostatic relationships between tau and HS are relatively nonspecific, a few studies have also identified the importance of specific HS sulfation patterns within the tau-HS connection. Prior works shown the crucial part of the 6-O-sulfation of HSPGs in the tau-HS connection by carrying out an SPR competition assay [39]. Moreover, 6-O-desulfated heparin showed the weakest competitive effect on tau binding to heparin immobilized on a chip among a variety of HS derivatives tested, including N-desulfated and 2-O-desulfated HS derivatives. NMR mapping showed that HS derivatives bound the second repeat motif (R2) in tau. Consistently, a knockout of 6-O-sulfotransferase also significantly reduced tau uptake by HEK293 cells [40]. Reduced intracellular tau uptake and tau cell surface binding inside a 3-O-sulfotransferase knockout cell collection compared with the wild-type cells suggest that tau protein is capable of realizing the less common 3-O-sulfation site of HS [41]. The importance of sulfation was further validated in competition assays performed by Zhao and coworkers3-O-sulfated low molecular excess weight HS (LMWHS) oligosaccharides experienced higher inhibitory effects within the tau-HS connection compared with those without sulfation in an SPR competition assay, further validating the specific part of 3-O-sulfation in tau-heparin relationships. Furthermore, 3-O-sulfation is definitely rare and small sulfation is found on HS chains, which is likely not responsible for any charge effects in HS chains. More likely, HS interacts with tau via a specific 3-O-sulfation of HS identified by both the PRR2 and R2 regions of tau instead of nonspecific electrostatic relationships. The tau-heparin connection has also been found to be chain size-dependent due to enhanced electrostatic relationships [40]. Knockouts of extension enzymes of the HSPG biosynthetic pathway, such as extension enzymes exostosin 1 (having a P301S mutation and display a series of pathological features of tauopathies, such as gliosis, synaptic loss, tangles, and neuronal loss over their lifetimes. Adapted from [51,52]. Note that with this model, no plaques were found; LTP, long-term potentiation; LTD, long-term major depression. (B) Both.Consequently, Gln is taken up by neurons and metabolized into Glu by neuron-related enzymes. extracellular tau uptake, which may not become restricted to one particular pathway [8,36]. For instance, smaller sized tau aggregates enter neurons inside a dynamin-dependent endocytosis pathway that is self-employed of actin polymerization [35]. For larger tau aggregates, actin-dependent macropinocytosis has been identified as the main pathway for internalization by neuronal cells [37]. However, the cellular access pathways of monomeric tau are highly dependent on the specific conformation and isoform. A recent study shown that monomeric tau could enter human being neurons via both the dynamin-dependent endocytosis process and through actin-dependent macropinocytosis, which could become controlled by HSPGs [35]. 3.1. The Effects of HSPGs within the Cellular Uptake of Tau Seeds HSPGs are highly expressed within the cell surface and have been identified as crucial cell-surface endocytosis receptors for tau internalization in various studies. Most recent research has focused on understanding the connection of heparan sulfate (HS) with tau protein in the structural level, which would provide a mechanistic understanding of how tau-HS connection regulates tau internalization during the progression of tau pathologies. HS-tau relationships look like driven primarily by electrostatic causes between negatively charged sulfo organizations on HS and positively charged lysines or arginines on tau protein [38]. Even though electrostatic interactions between tau and HS are relatively nonspecific, a few studies have also identified the importance of specific HS sulfation patterns Rabbit polyclonal to LACE1 around the tau-HS conversation. Prior works exhibited the crucial role of the 6-O-sulfation of HSPGs in the tau-HS conversation by performing an SPR competition assay [39]. Moreover, 6-O-desulfated heparin showed the weakest competitive effect on tau binding to heparin immobilized on a chip among a variety of HS derivatives tested, including N-desulfated and 2-O-desulfated HS derivatives. NMR mapping showed that HS derivatives bound the second repeat motif (R2) in tau. Consistently, a knockout of 6-O-sulfotransferase also significantly reduced tau uptake by HEK293 cells [40]. Reduced intracellular tau uptake and tau cell surface binding in a 3-O-sulfotransferase knockout cell line compared with the wild-type cells suggest that tau protein is capable of recognizing the less common 3-O-sulfation site of HS [41]. The importance of sulfation was further validated in competition assays performed by Zhao and coworkers3-O-sulfated low molecular weight HS (LMWHS) oligosaccharides had higher inhibitory effects around the tau-HS conversation compared with those without sulfation in an SPR competition KN-62 assay, further validating the specific role of 3-O-sulfation in tau-heparin interactions. Furthermore, 3-O-sulfation is usually rare and minor sulfation is found on HS chains, which is likely not responsible for any charge effects in HS chains. More likely, HS interacts with tau via a specific 3-O-sulfation of HS recognized by both the PRR2 and R2 regions of tau instead of nonspecific electrostatic interactions. The tau-heparin conversation has also been found to be chain size-dependent due to enhanced electrostatic interactions [40]. Knockouts of extension enzymes of the HSPG biosynthetic pathway, such as extension enzymes exostosin 1 (with a P301S mutation and display a series of pathological features of tauopathies, such as gliosis, synaptic loss, tangles, and neuronal loss over their lifetimes. Adapted from [51,52]. Note that in this model, no plaques were found; LTP, long-term potentiation; LTD, long-term depressive disorder. (B) Both microgliosis and astrogliosis are involved in the progression of tauopathies and abnormal neuronal activities, as indicated by phenotypic characterization of human tau pathology models [53]. Copyright ? 2021, John Wiley and Sons. As described in detail in the following sections, the development of tau-related pathologies has been postulated to follow spatiotemporal patterns and is characterized by multiple progressive stages, each with pathological features in the form of differential cellular behaviors and distinguished phenotypes (Physique 4). At the earliest stage, tau seeds formed by phosphorylated tau dissociate from microtubules spread along a transsynaptic pathway, involving the release of tau species in the synaptic cleft, with subsequent internalization by post-synaptic neurons [54]. Glial cells, on the other hand, adapt.