Bi M, Gladbach A, van Eersel J, Ittner A, Przybyla M, van Hummel A, Chua SW, van der Hoven J, Lee WS, Müller J, Parmar J, Jonquieres GV, Stefen H, Guccione E, Fath T, Housley GD, Klugmann M, Ke YD, Ittner LM. Tau exacerbates excitotoxic brain damage in an animal model of stroke. Nat Commun. 2017 Sep 7;8(1):473. PubMed.

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  1. This paper from the Ittner group is quite interesting, and primarily documents a novel "noncanonical" function of tau, i.e., a tau-dependent activation of the ERK pathway.

    The findings are in line with previous findings of this team (and others) showing that absence of tau provides some resistance to excitotoxicity, and that this mediates at least part of Aβ-mediated toxicity.

    The present study dissects in more depth the signaling mechanisms of this protective effect in tau knockout (tauKO) mice by showing that this goes though inactivation of the Ras/Raf/MEK/ERK pathway. This inactivation is associated with a post-synaptic accumulation of the synaptic protein SynGAP1, an endogenous inhibitor of Ras. 

    These data bring additional support for the "protective" role of lack of tau in several experimental settings (including in AD models), although it is not clear if a similar mechanism is involved in all of them.

    From a therapeutics point of view, it should be noted that protection provided by lack of tau is observed in models with chronic absence of tau (tauKO), and it is not yet obvious that acute reduction of tau (as could theoretically be done in patients) will have the same effects. Increasing SynGAP1, or more exactly, increasing its post-synaptic accumulation, would be a theoretical approach, but no data are provided on the effect of increasing SynGAP1 levels in in vivo models.

    The authors showed previously that Aβ-mediated toxicity in APP mice is reduced in APP/tauKO mice. It would now be quite interesting to confirm that changes are observed in the Ras/Raf/MEK/ERK pathway and in SynGAP1 localization in the latter mice, and that deficiencies in APP mice can be rescued by some degree of inactivation of ERK.

    View all comments by Jean-Pierre Brion

  2. Network hyperexcitability leading to rhythm disturbances in cortical and hippocampal microcircuits is a feature of many neurodegenerative disorders at some stage during their progressive course, and tau is a key switch in the appearance of abnormal information flow. Reduction of tau protein markedly and robustly interferes with the development of hyperexcitability in the context of epilepsy and stroke, yet paradoxically, tau deficiency on its own has not led to detectable neurological deficits, particularly in disease models where hyperphosphorylated tau is strongly linked to cognitive decline. Apparently, “no tau is better than bad tau.”

    View all comments by Jeffrey L. Noebels

  3. Tau is increasingly looking more like a sensitive but nonspecific biomarker of neuronal injury than a causative agent. Is it time for a paradigm shift?

    View all comments by Marcia Ratner

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