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Comparison of expression profiles of Control and CDDO-Im treatment microglia under IFN-gamma or Amyloid beta stimulation

ABSTRACT: Alzheimer’s disease (AD) is characterized by amyloid-beta (Amyloid beta) plaques and neurofibrillary tangles, accompanied by elevated oxidative stress and inflammation. Microglia, the resident macrophages in the brain, play a key protective role by clearing plaques and damaged neurons. NRF2 (Nuclear factor erythroid 2-related factor 2) is a master regulator of cytoprotection against oxidative stress, whose activation alleviates oxidative damage, neuroinflammation, and cognitive deficits in AD models. However, direct targets of NRF2 in microglia remain unclear. In this study, we demonstrate that NRF2 activation by CDDO-Im significantly suppresses inflammation in human microglial cells (HMC3) stimulated by IFN-gamma or Amyloid beta. Through integrative RNA-sequencing and ChIP-sequencing analysis of NRF2, we identified five representative NRF2 directly target genes involved in inflammation (e.g., IL6, CDK6) and another five in autophagy (e.g., TFE3, SQSTM1). Public single-cell transcriptomic data further underscored the critical role of microglia in NRF2-mediated autophagy regulation within AD brains. Our findings revealed new direct NRF2 target genes, highlighting dual role of NRF2 in suppressing inflammation and enhancing autophagy, thus providing novel insights for therapeutic interventions in AD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301269 | GEO | 2025/11/27

REPOSITORIES: GEO

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Project description:PLCγ2-P522R (phospholipase C gamma 2, proline 522 to arginine) is a protective variant that reduces the risk for late onset Alzheimer’s disease (LOAD). Recently, it was shown to decrease β-amyloid pathology in 5XFAD mouse model of AD. In this study, our goal was to investigate the protective functions of PLCγ2-P522R variant in less aggressive mouse model of AD as well as to assess underlying mechanisms at the molecular and cellular level using mouse and human microglia models. The effects of the protective PLCγ2-P522R variant on microglia activation, AD-related β-amyloid and neuronal pathologies, as well as behavioral changes were investigated in PLCγ2-P522R knock-in mice crossbred with an APP/PS1 mouse model of AD. Transcriptomic, proteomic, and functional studies were carried out in cultured and acutely isolated adult PLCγ2-P522R mouse microglia to study molecular mechanisms. Finally, microglia-like cell models generated from blood and skin biopsy samples of the PLCγ2-P522R variant carriers were employed to translate the key findings in human cells. Our results demonstrate that the PLCγ2-P522R variant reduces brain β-amyloid plaque burden of APP/PS1 mice. Simultaneously, PLCγ2-P522R variant increased non-proinflammatory microglia activation and microglia clustering around β-amyloid plaques, leading to reduced β-amyloid plaque-associated neuronal dystrophy. In cultured mouse primary microglia, PLCγ2-P522R variant decreased accumulation of large lipid droplets, reduced cell stress, and increased acute response to strong inflammatory stimuli. Transcriptomic and proteomic analyses in acutely isolated adult mouse microglia as well as in human monocyte-derived microglial cells showed that PLCγ2-P522R upregulates mitochondrial fatty acid oxidation and downregulates inflammatory/interferon signaling pathways. Accordingly, PLCγ2-P522R increased mitochondrial respiration in iPSC -derived microglial cells. Together, these findings suggest that PLCγ2-P522R variant exerts protection against AD-associated β-amyloid and neuronal pathologies via enhancing microglial barrier formation around β-amyloid plaques, but suppressing pro-inflammatory activation. Observed changes in fatty acid metabolism and mitochondrial flexibility as well as the downregulation of genes involved in inflammatory signaling pathways suggest that these protective effects of the PLCγ2-P522R variant are mediated through an anti-ageing mechanism.

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Comparison of expression profiles of Control and CDDO-Im treatment microglia under IFN-gamma or Amyloid beta stimulation

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