Meredith JE, Sankaranarayanan S, Guss V, Lanzetti AJ, Berisha F, Neely RJ, Slemmon JR, Portelius E, Zetterberg H, Blennow K, Soares H, Ahlijanian M, Albright CF. Characterization of Novel CSF Tau and ptau Biomarkers for Alzheimer's Disease. PLoS One. 2013;8(10):e76523. PubMed.

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  1. This study confirms the observation we made years ago that the majority of tau in cerebrospinal fluid (CSF) is not full-length, but consists of fragments that are detectable using N-terminal antibodies. This new study makes use of an extensive panel of well-characterized antibodies, as well as more comprehensive separation techniques, and has identified that there are several different tau fragments in CSF. The steps that result in cleavage of tau as it is released from cells, or after its release, have not been clarified, and it is possible that different enzymes are involved in tau release into CSF in patients with AD relative to controls. Therefore it is a worthwhile exercise to try to characterize and compare the fragments, as has been done in this new study. The researchers found that different antibody combinations gave slightly different results regarding the concentrations of tau that were measured in CSF, and that the degree of distinction between AD and controls varied slightly depending on which antibody combination was used. These findings could help develop the most AD-appropriate assay to measure CSF tau, and also evaluate if treatment interventions alter tau processing as it gets into CSF.

    View all comments by Douglas Galasko

  2. This study confirms what we (see Nov 2012 news story) and others (Johnson et al., 1997) have shown—that tau is secreted into the cerebrospinal fluid (CSF) in both healthy people and AD patients as fragments and not full-length. The study also confirms our findings that tau is enriched in AD patient cerebrospinal fluids over those of healthy controls.

    We also have disclosed that tau fragments are detected in the conditioned media from cortical neurons, in interstitial fluids, and CSF from mouse tauopathy models. Our findings are consistent with this new data.

    We’re gratified to see complementary data being published by others in the field. Subsequent to the Society for Neuroscience 2012 meeting, we selected our lead therapeutic tau antibody based on our secreted tau findings and on our hypothesis that secreted tau fragments drive tauopathy progression. As such, we developed assays to specifically measure secreted tau in in vivo tauopathy models and correlate secreted tau with efficacy endpoints. We are very pleased with the strong efficacy our lead antibody has demonstrated in these models. Given the program’s progress and advanced preclinical stage, we will be presenting this at SfN this year. I believe this presents a significant advance in the field by providing evidence that blocking secreted tau fragments reduces the development of tauopathy.

    View all comments by Irene Griswold-Prenner

  3. We did not study CSF-tau in our lab, but our thinking was always primed by the early findings of Gail Johnson, Doug Galasko, and colleagues that CSF tau consists essentially of N-terminal fragments in the range of 25 kD (Johnson et al., 1997). In the new publication, that paper is quoted as reference 33, but Doug's name does not appear because of the method of citation used by PlosOne and many other journals, which often leaves key authors unmentioned. It must be pleasing to Galasko and colleagues that their result was confirmed, now using much more refined methods. Time will tell whether the new knowledge will improve tau's value as an early biomarker. But it is interesting to compare this study with the recent paper by Dave Holtzman and colleagues (Yamada et al., 2011), who found full-length tau in the nanomolar range (1,000 times lower than the estimated intraneuronal levels) in the interstitial fluid, as measured by in-vivo microdialysis of mouse brains. The question therefore arises, where and how does the tau that winds up in the CSF loose its C-terminal half? This could be due to various extracellular proteases, difficult to judge as long as the cleavage sites are not known in detail. However, the question is relevant in the context of the current discussion on tau migration across cell barriers and the possibility that certain fragments and aggregates thereof transmit pathological conformations (see e.g. recent papers by the groups of Marc Diamond, Brad Hyman, or Karen Duff). This is in particular true for fragments derived from the C-terminal half of tau containing the repeat domain because this contains the aggregation signal in the form of short hexapeptide motifs (von Bergen et al., 2000). I therefore suspect that the interesting part of the story is yet to come—where are the missing C-terminal peptides, and what might they be doing?

    References:

    Johnson GV, Seubert P, Cox TM, Motter R, Brown JP, Galasko D. The tau protein in human cerebrospinal fluid in Alzheimer's disease consists of proteolytically derived fragments. J Neurochem. 1997 Jan;68(1):430-3. PubMed.

    Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, Binder LI, Mandelkow EM, Diamond MI, Lee VM, Holtzman DM. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci. 2011 Sep 14;31(37):13110-7. PubMed.

    von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow EM, Mandelkow E. Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5129-34. PubMed.

    View all comments by Eckhard Mandelkow

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