. Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer's Disease. Neuron. 2018 Dec 19;100(6):1337-1353.e5. Epub 2018 Nov 8 PubMed.

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  1. I have an academic soft spot for this study, as it perfectly validates some of our original findings on neurotoxic A1 reactive astrocytes in human AD and rodent tau models (Liddelow et al., 2018; Shi et al., 2018). In extensive work, Hui Zheng’s lab highlights that astrocyte C3 reactivity is paired with, and increasing with, Braak staging in patients. They also beautifully show that A1 C3 reactivity in GFAP+ astrocytes is present in PS19 mice, and that this reactivity is removed following ablation of the C3aR on microglia. This underscores an important feedback loop between disease-responsive microglia and astrocytes, which may be setting up a cascade in early disease stages.

    Interestingly, PS19 mice showed polarization to an A1-specific phenotype, not just upregulation of GFAP or broad upregulation of both A1 and A2 transcripts. Moreover, ablation of C3aR reverted DAM-activated microglia, which in response blocked only the A1 response but did not drive alternative activation states. This suggests a highly specific response to this genetic approach.  

    Key points in Litvinchuk et al.:

    1. Braak pairs with astrocyte activation in humans: higher Braak stage means more A1 neurotoxic reactive astrocytes.
    2. PS19 mice adequately recapitulate the DAM microglia phenomenon, and recapitulate the A1 neurotoxic reactive astrocyte phenotype seen in human patients.
    3. Ablating C3aR in microglia stops astrocyte activation, likely blocking a feedback loop that spirals out of control during disease progression.

    Moving forward, it will be interesting to see if this crosstalk initiates AD pathology/degeneration, or is simply a response to it. With the data sets provided by Hammond et al. and Schmiedel et al., we now have good baselines to start investigating this in both rodents and humans.

    References:

    . Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017 Jan 26;541(7638):481-487. Epub 2017 Jan 18 PubMed.

    . 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.

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