Just as jammed highways can shut down cities, disrupted intracellular trafficking along axons can trigger neuronal death and neurodegenerative disease. A paper in this week’s Journal of Neuroscience fleshes out a mechanism for how the protein tau might stymie axonal transport in Alzheimer’s disease and other tauopathies. Alzforum covered some of these data when they were presented at the 2009 Society for Neuroscience meeting in Chicago (ARF related conference story), and at a tau workshop earlier this spring in San Francisco (ARF related conference story). First author Nicholas Kanaan initiated the research while a postdoc in Lester Binder’s lab at the Feinberg School of Medicine at Northwestern University, Chicago, Illinois, and collaborated with Scott Brady and Gerardo Morfini at the University of Illinois, also in Chicago. The studies were completed at Michigan State University, Grand Rapids, where Kanaan now heads his own group.

Previously, the Binder group discovered that aggregated tau slows axonal transport by activating protein phosphatase (PP1) and glycogen synthase kinase 3 (GSK-3). The scientists pinned these activities to a phosphatase activation domain (PAD)—a stretch of 17 amino acids at tau’s N-terminal end—and showed that PAD was necessary and sufficient for tau to wreak havoc on trafficking in squid axoplasm motility assays (see Lapointe et al., 2008; ARF related conference story). The researchers generated a monoclonal antibody (Tau N-terminal 1, or TNT1) that recognizes tau with PAD exposed (ARF related conference story), and have used this antibody to probe postmortem brain tissue from AD patients. These experiments, detailed in the current paper, show that AD brains have more PAD-exposed tau than brains of age-matched controls. In addition, the scientists report that two disease-associated forms of tau (hyperphosphorylated tau recognized by the AT8 antibody, and a tau deletion mutant associated with frontotemporal dementia) react with the TNT1 antibody and inhibit axonal transport as soluble monomers—whereas wild-type tau monomers have no effect on transport and are not detected by TNT1. The findings support a model where disease-associated changes and mutations in tau promote PAD exposure, which in turn activates PP1 and GSK-3 and throws axonal trafficking out of whack. This “represents a direct mechanistic link between pathological changes in tau and neuronal dysfunction,” Kanaan wrote in an e-mail to ARF.

The findings also bolster the emerging idea that tau does much more than stabilize microtubules, that it may have a wide array of biological functions (see ARF related conference story for more on tau as a signal transduction protein). Work from Eckhard Mandelkow’s lab at the Max-Planck Unit for Structural Molecular Biology, Hamburg, Germany (see ARF related news story on Zempel et al., 2010), and also from Karen Hsiao-Ashe’s and Dezhi Liao’s labs at the University of Minnesota, Minneapolis (see ARF related news story on Hoover et al., 2010), blames tau toxicity on relocation of the protein from axons to the soma and dendrites. Research also suggests that tau inhibits axonal transport by clogging microtubules and interfering with the kinesin motor protein responsible for anterograde transport (Mandelkow et al., 2003; Seitz et al., 2002), but Kanaan noted that the current study suggests otherwise. “We show that tau-mediated inhibition of anterograde transport does not require microtubule binding, other domains of tau (e.g., microtubule binding repeat regions or the C-terminus), or tau aggregation,” he wrote. The data “suggest that tau may normally act as a signaling molecule that regulates local cargo delivery along neuronal processes (e.g., axons), and that the changes tau undergoes in disease cause an aberrant activation of this function leading to neuron dysfunction and degeneration.” (See full comment below.)—Esther Landhuis

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  1. Some studies suggest that tau inhibits axonal transport by clogging microtubules and interfering with the kinesin motor protein responsible for anterograde transport. However, our work clearly demonstrates that this is not the case in the context of the molecular mechanism we are studying. We show that tau-mediated inhibition of anterograde transport does not require microtubule binding, the other domains of tau (e.g., microtubule binding regions or the C-terminus), or tau aggregation, although aggregation is a means by which the phosphatase activation domain (PAD) can become exposed. The PAD peptide and N-terminal isoforms (6D and 6P) are key in demonstrating this point, as they do not bind microtubules and do not aggregate, but they do illicit significant inhibition of anterograde axonal transport via the PP1-GSK-3 signaling cascade. Our results are consistent with the concept that axonal transport is regulated by the activity of phosphotransferases on the motor proteins, and that these regulatory mechanisms go awry in numerous neurodegenerative diseases.

    The earliest form of tau pathology appears to be neuropil threads, which are aggregations of abnormal tau in the axons and dendrites of affected neurons. We found abnormal, PAD-exposed tau (double labeled with AT8 and TNT1 antibodies) within neuropil threads, suggesting the deleterious mechanisms identified in our studies are at work in these processes. While our work focuses on the anterograde transport in the axon of neurons, the data presented are likely applicable across most of the cellular compartments where tau pathology accumulates. As the disease progresses, the accumulation of abnormally modified and aggregated tau continues in the somatodendritic compartment of neurons where kinesin-based anterograde transport along microtubules is critical to normal function. A natural extension of our work is the prediction that kinesin-based transport along microtubules is disrupted by the accumulation of PAD-exposed tau and activation of the same signaling cascade in the cell body and dendrites of neurons.

    View all comments by Nicholas Kanaan

References

News Citations

  1. Chicago: Axonal Transport Not So Fast in Neurodegenerative Disease
  2. San Francisco: Gladstone Institute Hosts Tau Powwow
  3. San Francisco: Making Tau Toxic—Post-translational Changes Galore
  4. The Plot Thickens: The Complicated Relationship of Tau and Aβ
  5. Tau’s Synaptic Hats: Regulating Activity, Disrupting Communication

Paper Citations

  1. . The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity. J Neurosci Res. 2009 Feb;87(2):440-51. PubMed.
  2. . Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci. 2010 Sep 8;30(36):11938-50. PubMed.
  3. . Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010 Dec 22;68(6):1067-81. PubMed.
  4. . Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses. Neurobiol Aging. 2003 Dec;24(8):1079-85. PubMed.
  5. . Single-molecule investigation of the interference between kinesin, tau and MAP2c. EMBO J. 2002 Sep 16;21(18):4896-905. PubMed.

Further Reading

Papers

  1. . The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity. J Neurosci Res. 2009 Feb;87(2):440-51. PubMed.
  2. . Characterization of prefibrillar Tau oligomers in vitro and in Alzheimer disease. J Biol Chem. 2011 Jul 1;286(26):23063-76. PubMed.

Primary Papers

  1. . Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. J Neurosci. 2011 Jul 6;31(27):9858-68. PubMed.