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<p>Compared to individuals carrying two copies of the ε4 allele of apolipoprotein E (<i>APOE</i>), ε2 homozygotes have an approximate 99% reduction in late-onset Alzheimer’s disease (AD) risk. Here we develop a knock-in model that allows for an inducible ‘switch’ between risk and protective alleles (APOE4s2). Gene expression and proteomic analyses confirm that APOE4s2 mice synthesize E4 at baseline and E2 after tamoxifen administration. A whole-body allelic switch results in a metabolic profile resembling E2/E2 humans and drives AD-relevant alterations in the lipidome and single-cell transcriptome, particularly in astrocytes. Finally, when crossed to the 5xFAD background, astrocyte-specific E4 to E2 switching improves cognition, decreases amyloid pathology, lowers gliosis and reduces plaque-associated apolipoprotein E. Together, these data show that a short-term transition from <i>APOE4</i> to <i>APOE2</i> can broadly affect the cerebral transcriptome and lipidome, and that astrocyte-specific <i>APOE</i> replacement may be a viable strategy for future gene editing approaches to simultaneously reduce multiple AD-associated pathologies.</p>

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APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月11日

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  • Lesley R. Golden,
  • Dahlia S. Siano,
  • Isaiah O. Stephens,
  • Steven M. MacLean,
  • Kai Saito,
  • Georgia L. Nolt,
  • Jessica L. Funnell,
  • Akhil V. Pallerla,
  • Sangderk Lee,
  • Cathryn Smith,
  • Jing Chen,
  • Haining Zhu,
  • Clairity Voy,
  • Callie M. Whitus,
  • Gabriela Hernandez,
  • Brandon C. Farmer,
  • Kumar Pandya,
  • Dale O. Cowley,
  • Shannon L. Macauley,
  • Scott M. Gordon,
  • Josh M. Morganti,
  • Lance A. Johnson

摘要

Compared to individuals carrying two copies of the ε4 allele of apolipoprotein E (APOE), ε2 homozygotes have an approximate 99% reduction in late-onset Alzheimer’s disease (AD) risk. Here we develop a knock-in model that allows for an inducible ‘switch’ between risk and protective alleles (APOE4s2). Gene expression and proteomic analyses confirm that APOE4s2 mice synthesize E4 at baseline and E2 after tamoxifen administration. A whole-body allelic switch results in a metabolic profile resembling E2/E2 humans and drives AD-relevant alterations in the lipidome and single-cell transcriptome, particularly in astrocytes. Finally, when crossed to the 5xFAD background, astrocyte-specific E4 to E2 switching improves cognition, decreases amyloid pathology, lowers gliosis and reduces plaque-associated apolipoprotein E. Together, these data show that a short-term transition from APOE4 to APOE2 can broadly affect the cerebral transcriptome and lipidome, and that astrocyte-specific APOE replacement may be a viable strategy for future gene editing approaches to simultaneously reduce multiple AD-associated pathologies.