PubMed: 21734277

Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.
The Journal of neuroscience : the official journal of the Society for Neuroscience
Patterson KR | Binder LI | Song Y | Pigino GF | LaPointe NE | Andreadis A | Fu Y | Morfini GA | Brady ST | Kanaan NM

Evidence b0f8705340

Again, coperfusion of the PAD peptide with either I-2 (50 nM) (Fig. 5A) or ING-135 (100 nM) (Fig. 5B) anterograde FAT inhibition.

Evidence d6d7969cf0

As observed with 􏰁2–18 tau aggregates (LaPointe et al., 2009), monomeric 􏰁2–18 6D tau showed no effect on FAT (Fig. 4 A, D), demonstrating that PAD is necessary for 6D tau- mediated inhibition of anterograde FAT.

Evidence c96bccb6e5

The PAD peptide selectively in- hibited anterograde FAT (Fig. 4 B, D), but not retrograde FAT (Fig. 4B,E).

Evidence ca1f9b9bd9

Collectively, these data indicate that PAD is both necessary and sufficient to inhibit an- terograde FAT by activating the PP1–GSK3 cascade.

Evidence 60ea22d33d

P-c-Jun was dephosphorylated to a greater extent in PAD peptide-perfused axoplasms than their scrambled peptide- perfused counterpart (Fig. 5F ), suggesting that the PAD peptide induced activation of endogenous axoplasmic phosphatases.

Evidence ea11aa176c

A trend of elevated GSK3 activity (􏰈32%) relative to PKC activity ( p 􏰄 0.28, paired t test; n 􏰄 3) was observed for axoplasms incubated with the PAD peptide (mean 􏰄 4.9 􏰉 2.5), compared with those incubated with scram- bled peptide (mean 􏰄 3.7 􏰉 1.7), which supports the results from vesicle motility assays.

Evidence 4dd1cdf91b

To evaluate the relevance of these find- ings in human disease, we generated a novel monoclonal antibody, termed TNT1, which specifically recognizes PAD.

Evidence f8c026506a

These data indicated that increased PAD exposure, as revealed by TNT1 immunoreac- tivity, occurs early in AD and remains present throughout the disease process.

Evidence 5023cf296d

Together, these data suggest that increased PAD exposure represents an early event in AD pathogenesis and that AT8 may not be required for PAD ex- posure in situ.

Evidence 7b915a7e3e

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).

Evidence 214af08778

Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mech- anism involving activation of PP1 and GSK3 that is independent of microtubule binding.

Evidence 1ac1551664

Neither 6D nor 6P tau (Fig. 2D) had an effect on retrograde FAT

Evidence 9e499dad82

Soluble AT8 tau monomers inhibited anterograde FAT (Fig. 6 A, C), while retrograde trans- port was unaffected (Fig. 6 A, D). These data indicate that phos- phorylation of tau at the AT8 epitope, which is associated with hyperphosphorylation of tau in AD and other tauopathies, renders soluble monomeric tau capable of inhibiting antero- grade FAT.

Evidence 8c9c3774d4

Consistent with our model, 􏰁144 –273 tau monomers significantly inhibited antero- grade FAT (Fig. 6 B, C), while retrograde FAT remained unaf- fected (Fig. 6 B, D).Together, these data indicate that disease- associated modifications and mutations in tau that increase exposure of PAD promote activation of the PP1–GSK3 pathway and inhibition of anterograde FAT.

Evidence 7d07f50fcd

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


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