Litvinchuk A, Wan YW, Swartzlander DB, Chen F, Cole A, Propson NE, Wang Q, Zhang B, Liu Z, Zheng H. 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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NYU Langone
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.:
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:
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017 Jan 26;541(7638):481-487. Epub 2017 Jan 18 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.
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