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Alzheimer's-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in
Benjamin J Andreone1, Laralynne Przybyla2, Ceyda Llapashtica1
1Denali Therapeutics, South San Francisco, California, CA, USA.
Abstract:
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.
Insights
Phospholipase C gamma 2 (PLCγ2) is crucial for microglial function in Alzheimer's disease (AD), regulating survival and metabolism via TREM2 signaling and inflammation independently. Its dysfunction impacts neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglial dysfunction is implicated in Alzheimer's disease (AD) pathology.
- Genetic variants in TREM2 and PLCG2 are linked to AD risk.
- Mouse models suggest Trem2-dependent microglial roles in AD, but human relevance is unclear.
Purpose of the Study:
- To investigate the molecular mechanisms of TREM2 and PLCγ2 signaling in human microglia.
- To elucidate the role of PLCγ2 in microglial functions relevant to neurodegenerative diseases.
Main Methods:
- Utilized genetically engineered human induced pluripotent stem cell-derived microglia-like cells.
- Analyzed TREM2 and PLCγ2 signaling pathways.
- Examined microglial functions including cell survival, phagocytosis, debris processing, lipid metabolism, and inflammatory responses.
Main Results:
- TREM2 signals through PLCγ2 to regulate microglial survival, phagocytosis, debris processing, and lipid metabolism.
- Loss of TREM2 or PLCγ2 signaling results in shared transcriptional dysregulation.
- PLCγ2 independently regulates Toll-like receptor-mediated inflammatory responses.
Conclusions:
- PLCγ2 controls distinct microglial functions through both TREM2-dependent and -independent pathways.
- PLCγ2 activity is critical for maintaining normal microglial states and may be involved in the transition to neurodegenerative disease-associated states.
