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Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O'Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C, Butovsky O. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017 Sep 19;47(3):566-581.e9. PubMed.
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Comments
University of California San Diego
This is a fascinating paper. It provides substantial evidence for an ApoE-Trem2 pathway in mouse microglia that senses apoptotic neurons and induces a "neurodegenerative" phenotypic switch.
A particularly interesting finding is the evidence for a cell-autonomous role of microglia ApoE in driving this phenotype, based on its microglia-specific deletion.
A challenging aspect of this work is to clearly relate it to genetic studies in humans that indicate pathogenic consequences of loss of Trem2 function and protective consequences of lowered PU.1 expression. The loss of the homeostatic signature of microglia following phagocytosis of injected apoptotic neurons is intriguing but hard to interpret at this stage, in part because macrophage phagocytosis of apoptotic cells in the periphery is usually with tissue homeostatic roles.
It is thus not clear at this stage whether the "neurodegenerative" phenotype is pathogenic or an adaptive response. The main findings will thus certainly provoke substantial discussion and follow-up experiments about roles of this pathway in neurodegenerative disease. It will be particularly important to investigate whether this pathway operates in a similar manner in human microglia.
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