Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells

Oct 9, 2025Alzheimer's & dementia : the journal of the Alzheimer's Association

Alzheimer’s-linked PLCG2 gene changes affect the state and function of human stem cell-derived brain immune cells

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Abstract

Protective exhibit significant transcriptomic similarity to isogenic controls.

PLCG2 risk variant microglia show functionally reduced TREM2 expression compared to protective PLCG2 microglia.
Risk-conferring PLCG2 variants are associated with blunted inflammatory responses and increased cell death.
PLCG2-deficient microglia share a basal transcriptional profile with PLCG2 risk variant microglia.
Elevated cytokine secretion occurs in protective PLCG2 microglia following lipopolysaccharide (LPS) stimulation.
Distinct microglial transcriptomes driven by PLCG2 variants may contribute to Alzheimer's disease risk and protection.

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INTRODUCTION: Variants of phospholipase C gamma 2 (), 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 carrying the protective PLCG2or risk-conferring PLCG2variants, or loss of PLCG2, were generated to ascertain the impact on microglial transcriptome and function. P522R M28L

RESULTS: Protective PLCG2microglia showed significant transcriptomic similarity to isogenic controls. In contrast, risk-conferring PLCG2microglia shared similarities with PLCG2microglia, with functionally reduced TREM2 expression, blunted inflammatory responses, and increased proliferation and cell death. Uniquely, PLCG2microglia showed elevated cytokine secretion after lipopolysaccharide (LPS) stimulation and were protected from apoptosis. P522R M28L KO P522R

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).

Key numbers

80%

Increased Proliferation

Percentage of proliferative cells in and M28L variants after 24 hours.

87%

Cell Death Rate

Percentage of dead cells in -deficient after 48 hours of cytokine deprivation.

628 upregulated

Unique Differentially Expressed Genes

Number of upregulated genes in -deficient compared to wild-type.

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Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells

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