Udeochu JC, Amin S, Huang Y, Fan L, Torres ER, Carling GK, Liu B, McGurran H, Coronas-Samano G, Kauwe G, Mousa GA, Wong MY, Ye P, Nagiri RK, Lo I, Holtzman J, Corona C, Yarahmady A, Gill MT, Raju RM, Mok SA, Gong S, Luo W, Zhao M, Tracy TE, Ratan RR, Tsai LH, Sinha SC, Gan L. Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience. Nat Neurosci. 2023 May;26(5):737-750. Epub 2023 Apr 24 PubMed.

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Comments

  1. There is a lot here to be excited about, and Dr. Gan’s group should be commended for considering a role for tau-mitochondria interactions. Here, they add perspective to prior work that showed physical interactions occur, and these physical associations have functional consequences. If tau indeed messes with mitochondria, and induces a mitochondria DNA leak into the cytoplasm that triggers microglial activation via the cGAS-Sting pathway, that could have important implications for the basis of AD brain inflammation.

    I do think it is important to keep in mind that data generated by several groups also show a reverse relationship, in that mitochondria also mess with tau. Mitochondrial dysfunction increases neuronal cell tau expression, tau levels, phosphorylation, and splicing (Weidling et al., 2020). It is becoming increasingly clear that mitochondria interact with tau biology, as well as with APP, Aβ, and ApoE biology.

    References:

    Weidling IW, Wilkins HM, Koppel SJ, Hutfles L, Wang X, Kalani A, Menta BW, Ryan B, Perez-Ortiz J, Gamblin TC, Swerdlow RH. Mitochondrial DNA Manipulations Affect Tau Oligomerization. J Alzheimers Dis. 2020;77(1):149-163. PubMed.

    View all comments by Russell Swerdlow

  2. This is a very interesting and comprehensive piece of work diving into the mechanisms of microglial-induced neuronal toxicity in the context of tauopathy. It is in line with previous work by myself (Mancuso et al., 2019) and the Holtzman lab (Shi et al., 2017; Shi et al., 2019) that already reported a detrimental effect of microglia in mice carrying tau mutations.

    I find particularly interesting the finding that tau aggregates are able to induce mitochondrial damage in the microglia, and unleash their activation. As far as I know, this is the first time a mechanism as such is described.

    The second exciting observation is that Cgas deletion has a strong effect of neuronal genes related to resilience. In fact, looking carefully at the data, it appears that engagement of the Cgas pathways actually decreases the expression of resilience genes (when comparing P301S versus wild type mice). This may point to an interesting scenario where microglia are not actively inducing neuronal toxicity but, conversely, where they reduce the capacity of neurons to protect themselves against damage, therefore sensitizing the system to the development of dementia.

    This work also raises questions regarding the role of microglia linking amyloid and tau pathology. Is a scenario plausible where Aβ induces Cgas-IFN activation, leading to a diminished resilience of neurons to tau accumulation and resulting in neurodegeneration?

    References:

    Mancuso R, Fryatt G, Cleal M, Obst J, Pipi E, Monzón-Sandoval J, Ribe E, Winchester L, Webber C, Nevado A, Jacobs T, Austin N, Theunis C, Grauwen K, Daniela Ruiz E, Mudher A, Vicente-Rodriguez M, Parker CA, Simmons C, Cash D, Richardson J, NIMA Consortium, Jones DN, Lovestone S, Gómez-Nicola D, Perry VH. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain. 2019 Oct 1;142(10):3243-3264. PubMed.

    Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527. Epub 2017 Sep 20 PubMed.

    Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, Hoyle R, Holtzman DM. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019 Nov 4;216(11):2546-2561. Epub 2019 Oct 10 PubMed.

    View all comments by Renzo Mancuso

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