bp(GO:"axonal transport")

Entity

Name

axonal transport

Namespace

go

Namespace Version

20180921

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/go-names.belns

NFTs are formed by accumulation of hyperphosphorylated tau protein[7, 8]. Tau is a microtubule-binding protein whose function is to stabilize microtubules and facilitate fast axonal transport. Once highly phosphorylated, tau dissociates from microtubules and is prone to aggregate, forming paired helical fi laments that aggregate into NFTs PubMed:24590577

The trafficking of synaptic vesicles may also be negatively impacted by a-syn oligomers, which have been shown to decrease axonal transport by decreasing microtubule stability and impairing the interaction between kinesin and microtubules [128], as well as inhibiting tubulin polymerisation [20]. PubMed:28803412

perfusion of full-length WT tau monomers (2 􏰊M) (Fig. 1 A) had no effect on FAT in squid axoplasm (Fig. 2 A), while 6D and 6P tau monomers (2 􏰊M) significantly inhibited anterograde FAT when compared with WT tau monomer (Fig. 2 B, C) or buf- fer controls (data not shown). PubMed:21734277

While functional tau is an unfolded monomeric protein that stabilizes microtubules, regulates neurite growth, and monitors axonal transport of organelles (Medina and Avila, 2014), dysfunctional tau acquires a new toxic function PubMed:28420982

We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). These 4 markers are particularly useful in understanding potential posttraumatic events in CTE because PAD exposure impairs axonal transport (24), oligomers confer toxicity (28, 38–40), pS422 correlates with cognitive decline (15), and D421 truncated tau may be related to cell toxicity (41, 42). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE. PubMed:26671985

We developed a transgenic mouse, named TPR50, harboring human P301S tau. Tau phosphorylation in the hippocampus of TPR50 mice increased with age, particularly at S202/T205. Therefore, cognitive dysfunction in TPR50 mice may result from early MT dysfunction and impaired axonal transport rather than accumulation of insoluble tau and neurodegeneration. PubMed:24406748

Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT PubMed:21734277

The amount of Aβ produced could be altered by delayed axonal transport, as well as the precise species of metabolites of APPproduced— e.g., Aβ40 or 42, monomeric Aβ, or Aβ-oligomers or Aβ-derived diffusible ligands (ADDLs) (Lambert et al., 1998; Walsh et al., 2000). PubMed:12428809

Tau protein is a typical microtubule-associated protein (MAP) and thus is directly implicated in maintaining the integrity and stability of the micro- tubules and involved in axonal transport. On the other hand, recent findings propose a direct role for APP in axonal transport, as APP can link to kinesins moving along the microtubules (Kamal et al., 2001). PubMed:12428809

The microtubule-binding properties of tau protein are believed to be important for a number of processes, e.g., the formation and maintenance of axons and for fast axonal transport (FAT). PubMed:12428809

Tau protein is a typical microtubule-associated protein (MAP) and thus is directly implicated in maintaining the integrity and stability of the micro- tubules and involved in axonal transport. On the other hand, recent findings propose a direct role for APP in axonal transport, as APP can link to kinesins moving along the microtubules (Kamal et al., 2001). PubMed:12428809

Although much further work is needed, these additional data demonstrate that GSK-3β is intimately involved in the architecture of axons and other neuronal processes, providing indirect support for its role in tau-mediated con- trol of axonal transport. PubMed:12428809

The following proposition has been recently reit- erated that axonal transport in AD could become disrupted by increased neuronal concentrations of tau protein PubMed:12428809

Indeed, when lysosomal proteolysis is inhibited by blocking acidification or directly inhibiting cathepsins,axonal transport of autophagy-related compartments is selectively slowed and intermittently interrupted. PubMed:22908190

AVs and lysosomes constitute more than 95% of the organelles in dystrophic neuritic swellings in AD and AD mouse models, implying a cargo-specific defect in axonal transport, rather than a global one. PubMed:22908190

Aberrant phosphorylation and aggregation of Tau have been linked to axonal transport problems, synaptic malfunction and degeneration (6). PubMed:22611162

Aberrant phosphorylation and aggregation of Tau have been linked to axonal transport problems, synaptic malfunction and degeneration (6). PubMed:22611162

In addition, the aggregates may occupy space in the cell and thus directly interfere with axonal transport, leading to neurodegeneration PubMed:26631930

For example, hyperphosphorylated tau but not unphosphorylated tau can interact with the kinesin-associated protein JUN N‑terminal kinase-interacting protein 1 (JIP1) and thus impair the formation of the kinesin complex,which mediates axonal transport PubMed:26631930

It can do this by influencing the function of the motor proteins dynein and kinesin, which transport cargoes towards the minus ends (towards the cell body) and plus ends of microtubules (towards the axonal terminus), respectively (FIG. 3). PubMed:26631930

For example, hyperphosphorylated tau but not unphosphorylated tau can interact with the kinesin-associated protein JUN N‑terminal kinase-interacting protein 1 (JIP1) and thus impair the formation of the kinesin complex,which mediates axonal transport PubMed:26631930

Hyperphosphorylation of tau at the repeat domain reduces its microtubule binding, which may cause microtubule disassembly, leading to axonal transport deficits. PubMed:26631930

Another mutation (R5H or R5L) outside the microtubule-binding domain disrupts the binding of tau to the p150 subunit of the dynactin complex — an essential cofactor for the microtubule motor dynein —thereby possibly interfering with general axonal transport PubMed:26631930

Another mutation (R5H or R5L) outside the microtubule-binding domain disrupts the binding of tau to the p150 subunit of the dynactin complex — an essential cofactor for the microtubule motor dynein —thereby possibly interfering with general axonal transport PubMed:26631930

Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT PubMed:21734277

Tau protein is a typical microtubule-associated protein (MAP) and thus is directly implicated in maintaining the integrity and stability of the micro- tubules and involved in axonal transport. On the other hand, recent findings propose a direct role for APP in axonal transport, as APP can link to kinesins moving along the microtubules (Kamal et al., 2001). PubMed:12428809

Tau protein is a typical microtubule-associated protein (MAP) and thus is directly implicated in maintaining the integrity and stability of the micro- tubules and involved in axonal transport. On the other hand, recent findings propose a direct role for APP in axonal transport, as APP can link to kinesins moving along the microtubules (Kamal et al., 2001). PubMed:12428809

The following proposition has been recently reit- erated that axonal transport in AD could become disrupted by increased neuronal concentrations of tau protein PubMed:12428809

The amount of Aβ produced could be altered by delayed axonal transport, as well as the precise species of metabolites of APPproduced— e.g., Aβ40 or 42, monomeric Aβ, or Aβ-oligomers or Aβ-derived diffusible ligands (ADDLs) (Lambert et al., 1998; Walsh et al., 2000). PubMed:12428809

Although much further work is needed, these additional data demonstrate that GSK-3β is intimately involved in the architecture of axons and other neuronal processes, providing indirect support for its role in tau-mediated con- trol of axonal transport. PubMed:12428809

AVs and lysosomes constitute more than 95% of the organelles in dystrophic neuritic swellings in AD and AD mouse models, implying a cargo-specific defect in axonal transport, rather than a global one. PubMed:22908190

In addition, the aggregates may occupy space in the cell and thus directly interfere with axonal transport, leading to neurodegeneration PubMed:26631930