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An interesting paper, but failure to discuss relevant literature is a real problem

Posted by GFHall on 03 Feb 2012 at 01:15 GMT

The authors have generated a very nice mouse tauopathy model that approximates cell-autonomous tau expression of the sort that is required to study tau secretion and interneuronal tau transfer – something that has been demonstrated in situ in cell autonomous, non-transgenic tauopathy models (Kim et. al. 2010) but not in mouse tau transgenics models (but see Clavaguera et. al 2009).

One persistent difficulty in addressing problems such as this in widely used transgenic models has been that of “leak” expression of the transgene. Much (but not all) of the significance of the paper lies in the apparent solution of this problem. The results described certainly suggest that at least the aggregated state – if not tau protein itself – has been transferred across synapses. The fact that “recipient” neurons also showed some transgene expression prevents the authors from formally claiming that tau has been transferred (a claim which they are careful to avoid making), but it does seem very likely that this has in fact occurred. The result is actually quite similar to what Clavaguera et. al. showed in 2009, but here it has been accomplished without microinjection or other non-transgene related manipulations.

To me, the most interesting element in the paper is that the authors found more tau expression than expected in the brain regions to which the pathology had "propagated". Although this might be taken as a negation of their conclusion that the tau actually moved transsynaptically, I agree with their conclusion that interneuronal propagation of the protein most likely explains what they found. If that is so, the increased tau expression in these neurons could indicate the presence of a feedback mechanism in tau protein expression that might contribute to tau pathology spread and thus to the mechanism of tauopathy pathogenesis. This is certainly a novel and potentially significant implication of this paper, which marks an important advance in the modeling of tauopathy in murine transgenics.

However, I am surprised and concerned that the authors didn't discuss either of the above-mentioned papers. Transsynaptic tau movement in brain was demonstrated unambiguously in the lamprey model (Kim et. al. 2010a) and strongly implied in another mouse model (Clavaguera et. al. 2009), and its implications for the diagnosis, treatment and understanding of tauopathies such as Alzheimer’s Disease were discussed in detail in these papers. Moreover, tau secretion from and uptake into neurons have been characterized in both in situ and cell culture models (Kim et. al. 2010a,b, Frost et. al. 2009), most recently including mice (Yamada et. al. 2011). All of these papers are by now well known in the field, and provide essential background for the phenomenon being described in this paper, yet none were discussed. In particular, Kim et. al. 2010a and Clavaguera et. al. 2009, the most relevant existing studies to the results presented, were not even cited.

PLos One is a high impact journal covering a broad range of topics of high general significance, not a specialized journal devoted to technical advances in transgenic disease model generation. Failure to acknowledge and discuss important prior studies with an obvious bearing on the novelty and implications of the study being described distort the significance of the paper and invite misinterpretation. I hope that the authors and PLos will remedy this very serious oversight in what is otherwise an important, significant and extremely interesting paper.


Garth Hall

Associate Professor of Biology,
University of Massachusetts Lowell

Literature Cited:

Kim W, Lee S, Jung C, Ahmed A, Lee G, Hall GF. Interneuronal transfer of human tau between lamprey central neurons in situ. J. Alz. Dis. 2010a; 19:647-64.

Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, et al. Transmission and spreading of tauopathy in
transgenic mouse brain. Nat.Cell Biol. 2009; 11:909-13.

Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J. Biol.
Chem. 2009; 284:12845-52.

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 2010b; 584:3085-8.

Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J. Neurosci. 2011; 31:13110-7.

Competing interests declared: I am the senior author of several of the papers that I think should be discussed/cited in this article. It should be noted that I am also criticizing the omission of other key papers in the field, and that the authors have cited a relevant paper (14) from my laboratory.

RE: An interesting paper, but failure to discuss relevant literature is a real problem

kduff replied to GFHall on 03 Feb 2012 at 03:07 GMT

Hi Garth,
Just a quick comment in response to your post to explain why there are so few refs to the articles you indicate. We are of course aware of the small, but seminal body of work on tau "spread" that has been published but we decided to keep our paper very focused with respect to the discussion of tau spread between the EC and DGGcs in large part to prevent propagation of a confusion that I think has seeped into the field wrt what type of tau (parental or templated conformers) is actually spreading between cells. The current in vivo published literature does not test the specific mechanism we aimed to test - for example, the type of spread proposed in, for example, the Clavaguera paper almost certainly involves exogenously added (injected) human tau being taken up by cells at the site of injection, templating to the endogenous (human transgenic) tau in those, or very close by cells, and then passing on the newly templated form of tau (which will be derived more and more from the endogenous tau). To make the message of our paper as clear as possible that we are focusing on the transfer of molecules of tau across a synapse (and not propagation involving a templated intermediate), we decided not to perpetuate confusion in the field by including complicated discussions of the published papers, and instead we just focused on how the mapping informs on the mechanism of spread that we believe is involved in vivo, between neuroanatomically connected cells, in our model. This focus was not intended to omit, or diminish the importance of the previously published findings, just to try and focus on data relevant to what we were trying to show. Accordingly, the paper is brief and focused to try and make this point more clearly.
As anyone who has sat at the bar with me knows, I am more than happy to talk about all the fascinating aspects of tau spread, ad nauseum, but I thought very limited and focused discussion in this brief paper would benefit readers in understanding the take-home point. Hope that helps explain our reasoning -

No competing interests declared.

RE: RE: An interesting paper, but failure to discuss relevant literature is a real problem

GFHall replied to kduff on 03 Feb 2012 at 22:50 GMT

I think you are getting a bit ahead of the evidence here. You are not yet in a position to test whether templating (or any other spreading mechanism) is involved here or not - after all, even the source of the tau that is "spreading" is not entirely clear - especially in this specific context, since the cellular factors that limit lesion spread to a subset of connected neurons (and thus determine vulnerability) are still not known. While it does appear likely that tau transfer has occurred at synapses, you have not established it as a mechanism, since your study is entirely correlative. However, even if you had established that tau was actually transferred between neurons, at synapses, via a specific mechanism (you have established none of these), you would owe the readers and the research community at least a basic discussion of the existing literature as context to your work. Some of this work is directly relevant to whether an oligomer or templating-dependent mechanism for secretion and uptake might be involved. The paper by Frost et. al. 2009 addressed this directly; we also found that tau species that lack the MTBR are secreted via a different (and non-toxicity dependent) mechanism than is full length tau, and that anterograde transneuronal movement only occurred with tauopathy mutant tau, but not WT tau (Kim 2010). Tau was definitively transferred in this study because it was expressed cell-autonomously.

My concern with this is not that your work in unimportant or that it misrepresents anything directly; as I noted in my earlier post, I find aspects of this study quite intriguing. However, the way the paper is written, with no acknowledgment of the state of the field, makes it possible for a casual reader to read the paper and infer that this model and study represent a "paradigm shift" in the field when in fact they represent an important but incremental advance on current knowledge.

Even if your intention was not to diminish the work of others by failing to cite and discuss their highly relevant work, this is unquestionably the effect that this omission has had. I ask again that you and PLos rectify this immediately.

No competing interests declared.