This study is a very nice extension of earlier work on brain interstitial tau concentrations performed in humans following traumatic brain injury (Marklund et al., 2009). It is now important to examine tau homeostasis in normal conditions. Personally, I believe that extracellular tau in the absence of pathological processes may reflect neuroaxonal plasticity. This hypothesis is to some degree backed by studies on normal newborns who have very high levels of total and phosphorylated tau in their CSF (Mattsson et al., 2010). The first months after birth are characterized by extensive synaptic and neuronal remodeling, which may involve physiological tau phosphorylation and release of tau proteins from retracting and regrowing axons.

References:
Marklund N, Blennow K, Zetterberg H, Ronne-Engström E, Enblad P, Hillered L. Monitoring of brain interstitial total tau and beta amyloid proteins by microdialysis in patients with traumatic brain injury. J Neurosurg. 2009 Jun;110(6):1227-37. Abstract

Mattsson N, Sävman K, Osterlundh G, Blennow K, Zetterberg H. Converging molecular pathways in human neural development and degeneration. Neurosci Res. 2010 Mar;66(3):330-2. Abstract

View all comments by Henrik Zetterberg

This is an elegant study by the Holtzman group which clearly shows that yet another neurodegenerative disease-associated protein, thought to be cytosolic, is found extracellularly in the brain parenchyma. Using an optimized in-vivo microdialysis approach that causes minimal brain injury, in wild-type and P301S transgenic mice, Yamada and colleagues demonstrated that ISF tau concentration in interstitial fluid (ISF) is a lot higher than that in the cerebrospinal fluid (CSF). Interestingly, the levels between the two pools of tau did not appear to have a positive correlation. This finding is of great importance, especially when considering CSF tau as a biomarker for AD. Nonetheless, the presence of tau extracellularly is exciting since it suggests that a mechanism of propagation of tau aggregates could exist in tauopathies and related disorders. As such, it opens up new avenues for immunotherapy targeting extracellular tau in disease.

Similar to our studies with α-synuclein, the tau release was found to be physiological and in the absence of neurodegeneration. Still, one...  Read more

This is an elegant study by the Holtzman group which clearly shows that yet another neurodegenerative disease-associated protein, thought to be cytosolic, is found extracellularly in the brain parenchyma. Using an optimized in-vivo microdialysis approach that causes minimal brain injury, in wild-type and P301S transgenic mice, Yamada and colleagues demonstrated that ISF tau concentration in interstitial fluid (ISF) is a lot higher than that in the cerebrospinal fluid (CSF). Interestingly, the levels between the two pools of tau did not appear to have a positive correlation. This finding is of great importance, especially when considering CSF tau as a biomarker for AD. Nonetheless, the presence of tau extracellularly is exciting since it suggests that a mechanism of propagation of tau aggregates could exist in tauopathies and related disorders. As such, it opens up new avenues for immunotherapy targeting extracellular tau in disease.

Similar to our studies with α-synuclein, the tau release was found to be physiological and in the absence of neurodegeneration. Still, one important question that remains to be answered is the physiological relevance of extracellular tau. The study proposes the existence of a dynamic equilibrium between different species of intracellular and extracellular tau that is dependent on aggregate formation and accumulation. It is possible that a such a dynamic equilibrium exists to ensure neuronal homeostasis. In this respect, as also implied by our findings with α-synuclein, dysfunctions in the mechanism(s) regulating extracellular levels, such as secretion, re-uptake, or extracellular clearance, may affect neuronal survival. Optimizing in-vivo microdialysis probes to accurately detect and quantify oligomeric forms of such proteins in the ISF will shed more light onto the pathogenesis of Parkinson’s and Alzheimer’s diseases.

View all comments by Kostas Vekrellis

Dave Holtzman and colleagues have been using the very elegant method of microdialysis, which allowed them to collect ISF (interstitial fluid) from both wild-type and P301L tau transgenic mice, and to infuse tau aggregates. The paper by Yamada et al. further shows nicely that full-length tau is released into the ISF already under physiological conditions, and that in P301S tau transgenic mice, soluble tau levels in the ISF decrease as the mice become older. This is likely because soluble tau is trapped by the tau aggregates that form as the disease progresses. In CSF, in contrast, the tau concentration increases as the mice become older (as there is no peripheral aggregated tau that would trap soluble tau). The model that is put forward in Figure 7 explains very well the dynamics of tau ISF.

A whole series of follow-up experiments come immediately to mind. Starting with wild-type mice, one could expose these to all kinds of stress (anesthesia, food deprivation, or cold temperature) to determine whether these conditions, which cause an altered phosphorylation of...  Read more

Dave Holtzman and colleagues have been using the very elegant method of microdialysis, which allowed them to collect ISF (interstitial fluid) from both wild-type and P301L tau transgenic mice, and to infuse tau aggregates. The paper by Yamada et al. further shows nicely that full-length tau is released into the ISF already under physiological conditions, and that in P301S tau transgenic mice, soluble tau levels in the ISF decrease as the mice become older. This is likely because soluble tau is trapped by the tau aggregates that form as the disease progresses. In CSF, in contrast, the tau concentration increases as the mice become older (as there is no peripheral aggregated tau that would trap soluble tau). The model that is put forward in Figure 7 explains very well the dynamics of tau ISF.

A whole series of follow-up experiments come immediately to mind. Starting with wild-type mice, one could expose these to all kinds of stress (anesthesia, food deprivation, or cold temperature) to determine whether these conditions, which cause an altered phosphorylation of tau, would (permanently) alter extracellular tau deposition. Phosphorylation of tau has not been addressed yet, nor whether distinct phospho-tau species would reveal a correlation between ISF and CSF tau (a relationship not found for total tau). One will be able to determine which epitopes of tau are phosphorylated before and which ones only after tau aggregation. And obviously, as discussed in the paper, the question can be answered whether a tau-directed vaccination works at least in part by depleting extracellular pools of tau.

View all comments by Jurgen Goetz

This is a very ingenious demonstration that significant extracellular human tau levels exist and can be monitored in transgenic mice. It is particularly important because it opens the door to a detailed biochemical characterization of the secretion process in a widely used model system. The finding that CSF tau levels show a different dynamic than does ISF tau is also interesting, since it suggests the possible involvement of ependymal cell transcytosis in the genesis of CSF tau.

My lab has studied the mechanism of tau secretion for a number of years now. We are using cell-autonomous human tau expression in a non-transgenic lower vertebrate model. We have shown that secretion is modulated by aggregation inhibitors (Hall et al., 2002) and by presence of the P301L tauopathy mutation (Kim et al., 2010a); requires the amino terminus (Kim et al., 2010a); and is associated with the mislocation of membrane-associated tau to the dendrites (Lee et al., 2011). I am particularly interested in seeing how tau secretion mechanisms characterized using microdialysis in mouse models compare...  Read more

This is a very ingenious demonstration that significant extracellular human tau levels exist and can be monitored in transgenic mice. It is particularly important because it opens the door to a detailed biochemical characterization of the secretion process in a widely used model system. The finding that CSF tau levels show a different dynamic than does ISF tau is also interesting, since it suggests the possible involvement of ependymal cell transcytosis in the genesis of CSF tau.

My lab has studied the mechanism of tau secretion for a number of years now. We are using cell-autonomous human tau expression in a non-transgenic lower vertebrate model. We have shown that secretion is modulated by aggregation inhibitors (Hall et al., 2002) and by presence of the P301L tauopathy mutation (Kim et al., 2010a); requires the amino terminus (Kim et al., 2010a); and is associated with the mislocation of membrane-associated tau to the dendrites (Lee et al., 2011). I am particularly interested in seeing how tau secretion mechanisms characterized using microdialysis in mouse models compare with the Lamprey model data, given the complementary advantages of these in-situ systems.

The differences between extracellular fluid and CSF tau dynamics are also interesting in the context of our recent study (Saman et al., 2011) showing that the typical elevation of CSF Pthr181 tau levels in early AD (Braak Stage 3) is associated with increased ptau in CSF exosome fractions. That study also showed that the exosome pathway was involved in at least some of the tau secretion detected in cultured neuroblastoma cells. Most importantly, our results strongly suggest that passive tau release due to neuron death plays only a minor role in the genesis of CSF tau, especially early in the course of the disease.

The findings of Yamada et al. raise the possibility that it may be possible to use microdialysis to resolve the roles played by 1) tau secretion patterns, 2) changes to ependymal cell function in the genesis of early AD CSF tau increase, and 3) passive postmortem release from dead neurons or glia in experimentally manipulable systems.

References:
Hall GF, Lee S, Yao J. Neurofibrillary degeneration can be arrested in an in vivo cellular model of human tauopathy by application of a compound which inhibits tau filament formation in vitro. J Mol Neurosci. 2002 Dec;19(3):253-60. Abstract

Kim W, Lee S, Jung C, Ahmed A, Lee G, Hall GF. Interneuronal transfer of human tau between Lamprey central neurons in situ. J Alzheimers Dis. 2010;19(2):647-64. Abstract

Kim W, Lee S, Hall GF. Secretion of human tau fragments resembling CSF-tau in Alzheimer's disease is modulated by the presence of the exon 2 insert. FEBS Lett. 2010 Jul 16;584(14):3085-8. Abstract

Lee S, Kim W, Li Z and Hall GF (2011) Accumulation of vesicle-associated human tau in distal dendrites drives degeneration and tau secretion in an in situ cellular tauopathy model. In "Animal Models of Alzheimer's Disease" Int J Alz Dis, in press.

Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, Jackson B, McKee AC, Alvarez VE, Lee NC, Hall GF. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid (CSF) in early Alzheimer's Disease. J Biol Chem. 2011 Nov 4. Abstract

View all comments by Garth Hall