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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.
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iPierian
The past few years of tau research have provided strong evidence that endogenous tau secretion does occur in the absence of neuronal lysis. One of the next steps is to understand how a cytosolic protein such as tau is secreted. We and others in the field have defined this secretion as noncanonical, i.e., not secreted through the ER/Golgi network. Pooler et al., working in-vitro, and now Yamada et al. with this in-vivo study, are beginning to provide evidence that tau release is driven by the activity of presynaptic glutamatergic hippocampal neurons. It is interesting to note that although interstitial fluid (ISF) tau is elevated after induction of neuronal hyperactivity, the onset is delayed by hours (as compared to minutes-hours for the glucose/lactate changes in response to stimulation, i.e., K+) and persists long after glucose and lactate levels returned to baseline. This may suggest that increased ISF tau levels are a consequence of aberrant neuronal activity. As such, exploring this adaptive process may begin to help define the mechanism by which tau is secreted. Moving forward, it would be interesting to examine the biological consequences of tau secretion. There is accumulating evidence linking tau to epileptic seizures, for example. It would be interesting to see if secreted tau is linked to the increased seizure activity seen in Alzheimer’s disease.
References:
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.
Washington University
We agree with the comment by Irene Griswold-Prenner that given the results by both Pooler et al. and Yamada et al., it will be very interesting to determine whether secreted forms of tau are linked in any way to hyperexcitability and possibly seizures.
References:
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.
NIMH
This study presents the most clear-cut demonstration of the secretion of tau protein into the interstitial fluid (ISF) by neurons in intact brain, independent of cell death. The authors report converging evidence, which suggests that secretion of tau could be governed by and may occur as a result of "physiological" or close to physiological processes. Similar to Aβ release demonstrated by the same group (Cirito et al., 2008), secretion of tau is revealed to be considerably enhanced upon depolarization of neurons or under abnormally high network activity, e.g., driven by GABAA inhibitors. Surprisingly, the processes mediating release of Aβ and tau appear to rely on canonical SNARE proteins, known to drive the fusion of synaptic vesicles and neurotransmitter release. Indeed, inactivation of v-SNARE VAMP by tetanus toxin strongly suppresses the secretion of tau and Aβ (Pooler et al., 2013; Cirito et al., 2008). Although the authors suggest that the release of these peptides occurs at pre-synaptic terminals of excitatory synapses, no supportive data is provided. To this reader, it is difficult to imagine that peptides of several kD weight released into the cleft of glutamatergic excitatory synapses would escape so rapidly and with such ease into the ISF through layers of constraining barriers designed to contain molecules far smaller, such as aspartate and glutamate. While ectopic (i.e., out of active zones) or extra-synaptic release of tau and Aβ is an attractive possibility (similar to most of neuropeptides) and seems more feasible (based on reported ISF dynamics), it brings up an important question as to why the spread of both tau and Aβ tends to follow the pattern of neuronal connections in the brain.
References:
Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron. 2008 Apr 10;58(1):42-51. PubMed.
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.
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