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.

Reference:
Kanaan NM, Morfini GA, LaPointe NE, Pigino GF, Patterson KR, Song Y, Andreadis A, Fu Y, Brady ST, Binder LI. Pathogenic Forms of Tau Inhibit Kinesin-Dependent Axonal Transport through a Mechanism Involving Activation of Axonal Phosphotransferases. J Neurosci. 6 July 2011;31(27):9858-9868. Abstract