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PubMed: 12428809

Title
Axonal transport, tau protein, and neurodegeneration in Alzheimer's disease.
Journal
Neuromolecular medicine
Volume
2
Issue
None
Pages
151-65
Date
2002-01-01
Authors
Dewachter I | Terwel D | Van Leuven F

Evidence 5f0dac8e74
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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).

a(CHEBI:"amyloid-beta") association bp(GO:"axonal transport") View Subject | View Object

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bp(GO:"axonal transport") association a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence c6ad4f8911
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For the sake of completeness, we also refer to tau- 3R transgenic mice that developed another type of pathology in the hippocampus, e.g., straight fila- ments formed in aged mice older than 18 mo (Ishi- hara, 2001b), which was proposed to be relevant for AD, given the age-dependence.

a(HBP:"straight filaments") association path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HBP:"3R tau") increases a(HBP:"straight filaments") View Subject | View Object

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path(MESH:"Alzheimer Disease") association a(HBP:"straight filaments") View Subject | View Object

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Evidence 76600928a3
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. In ALS, accumulation of NFs is a prominent feature (Rouleau et al., 1996), and it has been demonstrated that NFs contribute heavily to the axonopathy of tau transgenic mice (Ishihara et al., 2001a).

a(MESH:"Intermediate Filaments") positiveCorrelation path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

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a(MESH:"Intermediate Filaments") negativeCorrelation a(MESH:Axons) View Subject | View Object

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a(MESH:Axons) negativeCorrelation a(MESH:"Intermediate Filaments") View Subject | View Object

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path(MESH:"Amyotrophic Lateral Sclerosis") positiveCorrelation a(MESH:"Intermediate Filaments") View Subject | View Object

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Evidence e0b39d435a
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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).

bp(GO:"axonal transport") association p(HGNC:MAPT) View Subject | View Object

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bp(GO:"axonal transport") association p(HGNC:APP) View Subject | View Object

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p(HGNC:MAPT) increases bp(GO:"microtubule cytoskeleton organization") View Subject | View Object

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p(HGNC:MAPT) association bp(GO:"axonal transport") View Subject | View Object

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p(HGNC:APP) association bp(GO:"axonal transport") View Subject | View Object

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Evidence 945e79175f
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The following proposition has been recently reit- erated that axonal transport in AD could become disrupted by increased neuronal concentrations of tau protein

bp(GO:"axonal transport") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"axonal transport") View Subject | View Object

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Evidence 7e5bb4780e
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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.

bp(GO:"axonal transport") association p(HGNC:GSK3B) View Subject | View Object

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p(HGNC:GSK3B) association bp(GO:"axonal transport") View Subject | View Object

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Evidence b7713bb26f
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However, it is believed that the secreted form of APP plays important roles in neuronal plasticity and survival (Mattson, 1997).

bp(GO:"negative regulation of neuron apoptotic process") association sec(p(HGNC:APP)) View Subject | View Object

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bp(GO:"regulation of neuronal synaptic plasticity") association sec(p(HGNC:APP)) View Subject | View Object

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sec(p(HGNC:APP)) association bp(GO:"regulation of neuronal synaptic plasticity") View Subject | View Object

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sec(p(HGNC:APP)) association bp(GO:"negative regulation of neuron apoptotic process") View Subject | View Object

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Evidence f37b799798
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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).

p(HGNC:MAPT) increases bp(GO:"axonal transport") View Subject | View Object

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p(HGNC:MAPT) increases bp(GO:"axon development") View Subject | View Object

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Evidence fc2ca68bff
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An important function of tau protein involves the stabilization and spacing of microtubules, proba- bly by linking to a number of tubulin subunits, thereby preventing or slowing microtubule depoly- merization (Drubin and Kirschner, 1986).

p(HGNC:MAPT) decreases bp(GO:"microtubule depolymerization") View Subject | View Object

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Evidence 3771c445ef
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Most recently, this role became even more puz- zling, since APP was implemented as a kinesin-1 receptor (Kamal et al., 2000; 2001). APP apparently binds to the light chain of kinesin-1, which itself is responsible for anterograde axonal transport and consists of two light chains (KLC) associated with two heavy chains (KIF5B).

p(HGNC:KLC1) increases bp(GO:"anterograde axonal transport") View Subject | View Object

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Evidence e2a9c8e6b0
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Other serine and threonine residues, not followed by proline, are phosphorylated by other protein kinases, including microtubule-affinity-regulating kinase (MARK) (Drewes et al., 1993), calcium/ calmodulin kinase II (CAMKII), cAMP-dependent kinase (PKA) (Johnson et al., 1992), and casein kinase II (Greenwood et al., 1994).

p(FPLX:CK2) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(FPLX:PKA) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(HGNC:CAMK2B) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(HGNC:MARK1) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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Evidence f5722329ee
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Among the specific “proline-dependent” kinases that can phosphorylate protein tau at dif- ferent sites in vitro, special attention is dedicated to glycogen-synthase kinase-3β (GSK-3β) (Michel et al., 1998), mitogen-activated protein kinase (MAPK) (Drewes et al., 1992), stress-activated protein kinases (SAPKs) (Goedert et al., 1997) and cyclin-dependent kinases (CDKs) including cdc2 and cdk5 (Baumann et al., 1993; Patrick et al., 1999).

p(FPLX:ERK) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(HGNC:CDK1) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(HGNC:CDK5) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(HGNC:GSK3B) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(HGNC:MAPK9) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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Evidence 0365df2b2d
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Tau protein is rapidly dephosphorylated by endogenous phosphatases such as protein phosphatases 1, 2A, and 2B (cal- cineurin) that are all present in the brain, and effec- tively dephosphorylate tau protein in vitro.

p(FPLX:PPP1) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(FPLX:PPP2) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(FPLX:PPP3) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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Evidence 4d9078613f
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TSubsequently, Wallerian degeneration and severe muscle wasting and motoric problems demon- strated the extensive neurodegeneration caused by the overexpression of human tau protein in a gene- dosage fashion.

p(HBP:"4R tau") increases path(MESH:"Wallerian Degeneration") View Subject | View Object

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p(HBP:"4R tau") increases path(MESH:"Muscular Atrophy") View Subject | View Object

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p(HBP:"4R tau") increases path(HP:Neurodegeneration) View Subject | View Object

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Evidence 1ae3ad0a2f
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Evidently, this argues for critical levels of protein tau-4R in the pathology of FTD and by exten- sion, in AD.

p(HBP:"4R tau") positiveCorrelation path(MESH:"Frontotemporal Dementia") View Subject | View Object

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p(HBP:"4R tau") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HBP:"4R tau") View Subject | View Object

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path(MESH:"Frontotemporal Dementia") positiveCorrelation p(HBP:"4R tau") View Subject | View Object

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Evidence 2f9e5fbe27
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Deletion of the C-terminus of APP695 or APPL, including the kinesin-binding region, disrupted axonal transport of APP695 and APPL.

p(HGNC:APPL) increases bp(GO:"anterograde axonal transport") View Subject | View Object

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Evidence a638610b54
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Neuronally overexpressed GSK-3β was demonstrated to hyperphosphorylate tau protein in vivo in the brain and spinal cord of double- transgenic mice (Spittaels et al., 2000) thereby reducing the amount of protein tau associated with microtubules by 50% (Spittaels et al., 2000).

p(HGNC:GSK3B) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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Annotations
MeSH
Brain
MeSH
Spinal Cord

p(HGNC:GSK3B) decreases complex(a(MESH:Microtubules), p(HGNC:MAPT)) View Subject | View Object

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Annotations
MeSH
Brain
MeSH
Spinal Cord

Evidence ae1c9cbd21
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More- over, the unbound tau protein was hyperphospho- rylated and especially at the AD-2 epitope, e.g., an epitope shown to contain serine 396 and serine 404.

p(HGNC:GSK3B) increases p(HGNC:MAPT, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404)) View Subject | View Object

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Annotations
MeSH
Brain
MeSH
Spinal Cord

p(HGNC:MAPT, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404)) association path(MESH:"Alzheimer Disease") View Subject | View Object

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Annotations
MeSH
Brain
MeSH
Spinal Cord

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404)) View Subject | View Object

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Annotations
MeSH
Brain
MeSH
Spinal Cord

Evidence dbdd0f7d54
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Surprisingly, the axonopathy was rescued in the tau x GSK-3β double-transgenic mice, together with a near-total normalization of the functional disabilities.

p(HGNC:GSK3B) increases a(MESH:Axons) View Subject | View Object

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