Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate
Katharina Cosker1, Anna Mallach1, Janhavi Limaye1
1Department of Neuroinflammation, University College London, Queen Square Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK.
Abstract:
The R47H variant of the microglial membrane receptor TREM2 is linked to increased risk of late onset Alzheimer's disease. Human induced pluripotent stem cell derived microglia (iPS-Mg) from patient iPSC lines expressing the AD-linked R47Hhet TREM2 variant, common variant (Cv) or an R47Hhom CRISPR edited line and its isogeneic control, demonstrated that R47H-expressing iPS-Mg expressed a deficit in signal transduction in response to the TREM2 endogenous ligand phosphatidylserine with reduced pSYK-pERK1/2 signalling and a reduced NLRP3 inflammasome response, (including ASC speck formation, Caspase-1 activation and IL-1beta secretion). Apoptotic cell phagocytosis and soluble TREM2 shedding were unaltered, suggesting a disjoint between these pathways and the signalling cascades downstream of TREM2 in R47H-expressing iPS-Mg, whilst metabolic deficits in glycolytic capacity and maximum respiration were reversed when R47H expressing iPS-Mg were exposed to PS+ expressing cells. These findings suggest that R47H-expressing microglia are unable to respond fully to cell damage signals such as phosphatidylserine, which may contribute to the progression of neurodegeneration in late-onset AD.
Insights
The R47H TREM2 variant impairs microglial response to phosphatidylserine, a key signal in Alzheimer's disease. This deficit in TREM2 signaling may drive neurodegeneration in late-onset Alzheimer's disease.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- The TREM2 R47H variant is a significant risk factor for late-onset Alzheimer's disease (AD).
- Microglia, the brain's immune cells, play a crucial role in AD pathogenesis.
- Understanding TREM2's function in microglia is vital for AD research.
Purpose of the Study:
- To investigate the functional consequences of the TREM2 R47H variant in human induced pluripotent stem cell-derived microglia (iPS-Mg).
- To determine how the R47H variant affects microglial signaling pathways and cellular responses to damage signals.
Main Methods:
- Generated iPS-Mg from patient iPSC lines with heterozygous (R47Hhet) and homozygous (R47Hhom) TREM2 variants, alongside control lines.
- Assessed TREM2 signaling, inflammasome activation (NLRP3), and metabolic function in response to phosphatidylserine (PS).
- Evaluated phagocytosis of apoptotic cells and soluble TREM2 shedding.
Main Results:
- R47H-expressing iPS-Mg showed impaired signal transduction upon phosphatidylserine stimulation, including reduced pSYK-pERK1/2 signaling.
- NLRP3 inflammasome activation, measured by ASC speck formation, Caspase-1 activation, and IL-1beta secretion, was reduced in R47H-expressing iPS-Mg.
- Metabolic deficits in glycolytic capacity and respiration were observed but reversed upon exposure to PS+ cells; apoptotic cell phagocytosis and TREM2 shedding were unaltered.
Conclusions:
- TREM2 R47H variant leads to a deficit in microglial response to phosphatidylserine, a critical damage signal.
- This impaired signaling may contribute to neuroinflammation and neurodegeneration in late-onset Alzheimer's disease.
- Findings highlight a specific functional impairment in microglia associated with the AD-risk R47H TREM2 variant.
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