| Autor: |
Andreone BJ; Denali Therapeutics, South San Francisco, California, CA, USA., Przybyla L; Denali Therapeutics, South San Francisco, California, CA, USA. laralynne.przybyla@gmail.com., Llapashtica C; Denali Therapeutics, South San Francisco, California, CA, USA., Rana A; Denali Therapeutics, South San Francisco, California, CA, USA., Davis SS; Denali Therapeutics, South San Francisco, California, CA, USA., van Lengerich B; Denali Therapeutics, South San Francisco, California, CA, USA., Lin K; Denali Therapeutics, South San Francisco, California, CA, USA., Shi J; Denali Therapeutics, South San Francisco, California, CA, USA., Mei Y; Denali Therapeutics, South San Francisco, California, CA, USA., Astarita G; Denali Therapeutics, South San Francisco, California, CA, USA., Di Paolo G; Denali Therapeutics, South San Francisco, California, CA, USA., Sandmann T; Denali Therapeutics, South San Francisco, California, CA, USA., Monroe KM; Denali Therapeutics, South San Francisco, California, CA, USA., Lewcock JW; Denali Therapeutics, South San Francisco, California, CA, USA. lewcock@dnli.com. |
| Abstrakt: |
Human genetic data indicate that microglial dysfunction contributes to the pathology of Alzheimer's disease (AD), exemplified by the identification of coding variants in triggering receptor expressed on myeloid cells 2 (TREM2) and, more recently, in PLCG2, a phospholipase-encoding gene expressed in microglia. Although studies in mouse models have implicated specific Trem2-dependent microglial functions in AD, the underlying molecular mechanisms and translatability to human disease remain poorly defined. In this study, we used genetically engineered human induced pluripotent stem cell-derived microglia-like cells to show that TREM2 signals through PLCγ2 to mediate cell survival, phagocytosis, processing of neuronal debris, and lipid metabolism. Loss of TREM2 or PLCγ2 signaling leads to a shared signature of transcriptional dysregulation that underlies these phenotypes. Independent of TREM2, PLCγ2 also signals downstream of Toll-like receptors to mediate inflammatory responses. Therefore, PLCγ2 activity regulates divergent microglial functions via distinct TREM2-dependent and -independent signaling and might be involved in the transition to a microglial state associated with neurodegenerative disease. |
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