. Tau Kinetics in Neurons and the Human Central Nervous System. Neuron. 2018 Mar 21;97(6):1284-1298.e7. PubMed.

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  1. Sato et al. shed new light on the mechanisms of tau proteins in the human CNS. Interestingly, the authors presented strong evidence for tau production as an active process in Alzheimer’s disease. This work brings us from static data points to dynamic measures that may have better predictive potential as we establish mechanistic links between amyloid and tau pathology. These findings will also help elucidate the underlying mechanisms of different tauopathies. They will also inform the design of future clinical trials, especially those testing tau-based therapies.

    View all comments by Yakeel T. Quiroz
  2. This really exciting and groundbreaking study from the Bateman laboratory and colleagues introduces a powerful new set of methodologies highly relevant to efforts to understand human tau biology both in the clinical setting and with ex vivo stem cell models.

    By defining the steady-state turnover kinetics of tau using their SILK methodology, this study lays the foundation for future studies seeking to test experimental therapeutic agents that may enhance the rate of tau clearance or its production, as well as to compare the kinetic and metabolic properties of tau across different tauopathies beyond Alzheimer’s disease. That the half-lives of different tau isoforms and post-translationally modified forms are variable is fascinating, begging the question of what the underlying molecular mechanisms are that control the kinetics and stability of different tau species in the CNS.

    A critical observation for the field’s efforts working on patient-derived stem cell models was the recognition that the intracellular profile of iPSC-derived cortical neurons was strikingly similar to that observed in human brain despite the relative immature nature of six-week differentiated neurons.

    However, the half-life of tau in control human iPSC-derived neurons was ~3.5-fold shorter that in humans (~6.7 days versus 23 days), pointing to differences in the metabolism of tau in ex vivo and in vivo systems.

    One area for future investigation will be the impact the detection of peptides by IP-LC-MS methodology will have on our understanding of post-translational modifications of tau. Given the plethora of different tau modifications, these may impact the sensitivity of the assay to detect different peptides. Here, the ability to readily probe these modifications using human iPSC technology will afford a detailed exploration of these variables.

    Overall, establishing if and how these tau profiles vary as a function of specific causal mutations for disease will be an exciting future direction for the application of this SILK technology. Moreover, as the mechanisms controlling tau proteolysis remain poorly understood, yet are at the heart of many ongoing therapeutic efforts, the quantitative and scalable nature of these assays provides an invaluable new tool to facilitate more detailed mechanistic studies.

    View all comments by Stephen Haggarty
  3. These very interesting human results are in line with and predicted from the CSF analyses of APP transgenic mouse models (Maia et al., 2013; Schelle et al., 2016).

    References:

    . Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci Transl Med. 2013 Jul 17;5(194):194re2. PubMed.

    . Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition. Alzheimers Dement. 2016 Oct 14; PubMed.

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