Scholarlink

Background <p>The ε4 isoform of apolipoprotein E (ApoE) is the most significant genetic risk factor for Alzheimer’s disease. Glial cells are the main source of ApoE in the brain, and in microglia, the ε4 isoform of ApoE has been shown to impair mitochondrial metabolism and the uptake of lipids and Aβ42. However, whether the ε4 isoform alters autophagy or lysosomal activity in microglia in basal and inflammatory conditions is unknown.</p> Methods <p>Altogether, microglia-like cells (iMGs) from eight <i>APOE</i>3/3 and six <i>APOE</i>4/4 human induced pluripotent stem cell (iPSC) lines were used in this study. The responses of iMGs to Aβ42, LPS and IFNγ were studied by metabolomics, proteomics, and functional assays.</p> Results <p>Here, we demonstrate that iMGs with the <i>APOE</i>4/4 genotype exhibit reduced basal pinocytosis levels compared to <i>APOE</i>3/3 iMGs. Inflammatory stimulation with a combination of LPS and IFNγ or Aβ42 induced PI3K/AKT/mTORC signaling pathway, increased pinocytosis, and blocked autophagic flux, leading to the accumulation of sequestosome 1 (p62) in both <i>APOE</i>4/4 and <i>APOE</i>3/3 iMGs. Exposure to Aβ42 furthermore caused lysosomal membrane permeabilization, which was significantly stronger in <i>APOE</i>4/4 iMGs and positively correlated with the secretion of the proinflammatory chemokine IL-8. Metabolomics analysis indicated a dysregulation in amino acid metabolism, primarily L-glutamine, in <i>APOE</i>4/4 iMGs.</p> Conclusions <p>Overall, our results suggest that inflammation-induced metabolic reprogramming places lysosomes under substantial stress. Lysosomal stress is more detrimental in <i>APOE</i>4/4 microglia, which exhibit endo-lysosomal defects.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Inflammation-induced lysosomal dysfunction in human iPSC-derived microglia is exacerbated by APOE 4/4 genotype

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月2日

查看全文
  • Marianna Hellén,
  • Isabelle Weert,
  • Stephan A. Müller,
  • Noora Räsänen,
  • Pinja Kettunen,
  • Šárka Lehtonen,
  • Michael Peitz,
  • Klaus Fließbach,
  • Mari Takalo,
  • Marja Koskuvi,
  • Stefan F. Lichtenthaler,
  • Ville Leinonen,
  • Alfredo Ramirez,
  • Olli Kärkkäinen,
  • Mikko Hiltunen,
  • Jari Koistinaho,
  • Taisia Rõlova

摘要

Background

The ε4 isoform of apolipoprotein E (ApoE) is the most significant genetic risk factor for Alzheimer’s disease. Glial cells are the main source of ApoE in the brain, and in microglia, the ε4 isoform of ApoE has been shown to impair mitochondrial metabolism and the uptake of lipids and Aβ42. However, whether the ε4 isoform alters autophagy or lysosomal activity in microglia in basal and inflammatory conditions is unknown.

Methods

Altogether, microglia-like cells (iMGs) from eight APOE3/3 and six APOE4/4 human induced pluripotent stem cell (iPSC) lines were used in this study. The responses of iMGs to Aβ42, LPS and IFNγ were studied by metabolomics, proteomics, and functional assays.

Results

Here, we demonstrate that iMGs with the APOE4/4 genotype exhibit reduced basal pinocytosis levels compared to APOE3/3 iMGs. Inflammatory stimulation with a combination of LPS and IFNγ or Aβ42 induced PI3K/AKT/mTORC signaling pathway, increased pinocytosis, and blocked autophagic flux, leading to the accumulation of sequestosome 1 (p62) in both APOE4/4 and APOE3/3 iMGs. Exposure to Aβ42 furthermore caused lysosomal membrane permeabilization, which was significantly stronger in APOE4/4 iMGs and positively correlated with the secretion of the proinflammatory chemokine IL-8. Metabolomics analysis indicated a dysregulation in amino acid metabolism, primarily L-glutamine, in APOE4/4 iMGs.

Conclusions

Overall, our results suggest that inflammation-induced metabolic reprogramming places lysosomes under substantial stress. Lysosomal stress is more detrimental in APOE4/4 microglia, which exhibit endo-lysosomal defects.