Numerous studies have reported that tau travels between neurons, but scientists are unsure how the protein exits the cell. In the February 17 Journal of Experimental Medicine, researchers led by David Holtzman at Washington University in St. Louis provide the first in-vivo evidence that neurons in healthy mice release monomeric tau in response to excitatory electrical activity. Whether pathologic forms of tau hijack this physiologic process to spread through the brain remains to be seen.
“This is an exciting paper. It ties into the idea that tau propagates along neural circuits, which is what we see in human disease and animal models,” said Amy Pooler at King’s College London. She was not involved in the research, but has reported similar activity-dependent tau release from neurons in vitro (see Aug 2013 conference story; Pooler et al., 2013).
Pathogenic forms of tau are now widely believed to propagate themselves through the brain by slipping from one neuron to another along axonal pathways. This requires the protein to travel through the extracellular space (see, e.g., Feb 2012 news story; Aug 2013 conference story). Holtzman and colleagues previously developed a method to measure monomers of tau in the interstitial fluid (ISF) in the brain by sampling it with a microdialysis probe inserted into the hippocampus of wild-type mice (see Sep 2011 news story).
In the current paper, first author Kaoru Yamada used the same technique to determine whether neuronal activity regulated ISF tau. Yamada tricked neurons to fire in awake, active mice by infusing potassium through the microdialysis probe. In response, ISF tau shot up two- to threefold over several hours, dropping as tau diffused away from the probe site. Other means of stimulating neurons, such as adding the glutamate receptor agonist NMDA, or triggering glutamate release from presynaptic terminals, produced similar results, demonstrating that excitatory presynaptic activity controlled the phenomenon. “It surprised me that a cytoplasmic protein would be regulated by synaptic activity in this way,” Holtzman told Alzforum. “We still don’t know why this happens.”
Surprisingly, blocking neuronal activity did not noticeably lower ISF tau. The authors wondered if that was because the protein just stuck around for long periods. To explore this hypothesis, Yamada and colleagues used transgenic mice developed by co-authors Eva and Eckhard Mandelkow at the German Center for Neurodegenerative Diseases (DZNE) in Bonn (see Feb 2011 news story). The animals express monomeric human tau under the control of the inducible doxycycline promoter. When the authors switched off tau production, it took 11 days for ISF protein levels to drop by half, confirming that tau clears quite slowly.
Holtzman's group reported previously that neuronal activity also regulates Aβ release in vivo (see Oct 2003 news story; Dec 2005 news story; Sep 2008 news story; Aug 2011 news story). He pointed out that activity affects Aβ less than tau, the former inching up by only 30 or 40 percent. The mechanism may also be different, as Aβ release depends on endosome recycling (see Apr 2008 news story), whereas researchers believe tau escapes the cell by other means, Holtzman said. It is not known if there is any connection between Aβ and tau release.
These experiments did not measure tau aggregates, or examine whether ISF tau was modified or truncated in any way. Other work has suggested that aggregated, hyperphosphorylated, fragmented, or pathologically folded forms of tau spread through the brain (see, e.g., Nov 2012 conference story; Feb 2013 news story; Nov 2013 news story). In future studies, Holtzman and colleagues will look more closely at what forms of tau populate the ISF and how they behave. Pooler suggested that scientists could use that information to tailor immunotherapies that mop up pathogenic tau while leaving healthy protein alone (see Sep 2013 news story).—Madolyn Bowman Rogers.
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- Pooler AM, Phillips EC, Lau DH, Noble W, Hanger DP. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 2013 Apr;14(4):389-94. PubMed.
- Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, Jiang H, Cirrito JR, Patel TK, Hochgräfe K, Mandelkow EM, Holtzman DM. Neuronal activity regulates extracellular tau in vivo. J Exp Med. 2014 Mar 10;211(3):387-93. Epub 2014 Feb 17 PubMed.