Alzheimer's disease-associated PLCG2 variants alter microglial state and function in human induced pluripotent stem
Logan M Bedford1,2, Kaylee D Tutrow1,3, Karly Hooper3
1Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Introduction:
Variants of phospholipase C gamma 2 (PLCG2), a key microglial immune signaling protein, are genetically linked to Alzheimer's disease (AD) risk. Understanding how PLCG2 variants alter microglial function is critical for identifying mechanisms that drive neurodegeneration or resiliency in AD.
Methods:
Induced pluripotent stem cell (iPSC) -derived microglia carrying the protective PLCG2P522R or risk-conferring PLCG2M28L variants, or loss of PLCG2, were generated to ascertain the impact on microglial transcriptome and function.
Results:
Protective PLCG2P522R microglia showed significant transcriptomic similarity to isogenic controls. In contrast, risk-conferring PLCG2M28L microglia shared similarities with PLCG2KO microglia, with functionally reduced TREM2 expression, blunted inflammatory responses, and increased proliferation and cell death. Uniquely, PLCG2P522R microglia showed elevated cytokine secretion after lipopolysaccharide (LPS) stimulation and were protected from apoptosis.
Discussion:
These findings demonstrate that PLCG2 variants drive distinct microglia transcriptomes that influence microglial functional responses that could contribute to AD risk and protection. Targeting PLCG2-mediated signaling may represent a powerful therapeutic strategy to modulate neuroinflammation.
Highlights:
The impact of Alzheimer's disease protective- and risk-associated variants of phospholipase C gamma 2 (PLCG2) on the transcriptome and function of induced pluripotent stem cell (iPSC) -derived microglia was investigated. PLCG2 risk variant microglia exhibited a basal transcriptional profile similar to PLCG2-deficient microglia but significantly different from isotype control and the transcriptionally similar PLCG2 protective variant microglia. PLCG2 risk variant and PLCG2-deficient microglia show decreased levels of triggering receptor expressed on myeloid cells 2 (TREM2). The differential transcriptional pathways of protective and risk-associated PLCG2 variant microglia functionally affect proliferation, apoptosis, and immune response. Protective PLCG2 microglia show resilience to apoptosis and increased cytokine/chemokine secretion upon exposure to lipopolysaccharide (LPS).
Insights
Genetic variants in phospholipase C gamma 2 (PLCG2) impact Alzheimer's disease risk by altering microglial function. Understanding these PLCG2 variants is key to developing new therapies for neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Phospholipase C gamma 2 (PLCG2) is a key microglial immune signaling protein.
- Genetic variants in PLCG2 are linked to Alzheimer's disease (AD) risk.
- Investigating PLCG2 variant effects on microglia is crucial for understanding AD pathogenesis.
Purpose of the Study:
- To determine the impact of protective (PLCG2P522R) and risk-conferring (PLCG2M28L) PLCG2 variants on microglial transcriptome and function.
- To compare the effects of PLCG2 variants with PLCG2 deficiency in microglia.
Main Methods:
- Generation of induced pluripotent stem cell (iPSC)-derived microglia with specific PLCG2 variants or knockout (KO).
- Analysis of microglial transcriptome and functional responses.
- Assessment of TREM2 expression, inflammatory responses, proliferation, and apoptosis.
Main Results:
- PLCG2P522R microglia resembled controls transcriptomically.
- PLCG2M28L microglia showed similarities to PLCG2KO microglia, with reduced TREM2, blunted inflammation, and altered proliferation/apoptosis.
- PLCG2P522R microglia exhibited enhanced cytokine secretion and apoptosis resistance upon LPS stimulation.
Conclusions:
- PLCG2 variants distinctly alter microglial transcriptomes and functions, influencing AD risk and protection.
- Targeting PLCG2 signaling offers a potential therapeutic strategy for neuroinflammation in AD.
- Differential microglial responses mediated by PLCG2 variants impact AD pathogenesis.
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