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Humanized ApoE4 combined with AppNL-F mutations in mice caused hypoactivity and neuroinflammation. Reduced Aβ plaques in these mice highlight species-specific differences, emphasizing the need for humanized models in Alzheimer

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Humanized Apolipoprotein E4 (ApoE4) is a significant genetic risk factor for late-onset Alzheimer's Disease (AD).
  • ApoE4 is linked to synaptic dysfunction, neuroinflammation, and impaired amyloid-beta (Aβ) clearance.
  • The AppNL-F knock-in mouse model replicates human Aβ pathophysiology while maintaining native gene regulation.

Purpose of the Study:

  • To investigate the combined effects of AppNL-F mutations and humanized ApoE4 on AD pathogenesis.
  • To address challenges in modeling human ApoE biology in mice.
  • To advance translational insights into AD.

Main Methods:

  • Generated four genotypes: ApoE4/AppNL-F (E4NLF), ApoE4 (E4), AppNL-F (NLF), and wild-type (WT).
  • Utilized open field behavioral testing with machine learning analysis.
  • Quantified Aβ plaques and microglial reactivity via immunohistochemistry.
  • Measured soluble Aβ42/40 levels using ELISA and identified differentially expressed genes (DEGs) via snRNA-seq.

Main Results:

  • E4NLF mice exhibited hypoactivity, impaired habituation, and increased slow movements.
  • E4NLF mice showed significantly fewer hippocampal Aβ plaques compared to NLF mice.
  • Microglia displayed activation near plaques in both NLF and E4NLF genotypes.
  • Reduced Ttr expression in E4NLF astrocytes and microglia suggested disrupted Aβ clearance.
  • Excitatory neurons showed the highest number of DEGs in E4NLF mice.

Conclusions:

  • Combining ApoE4 and AppNL-F mutations induces distinct AD-related phenotypes, including neuroinflammation and impaired glial function.
  • Reduced Aβ plaques in E4NLF mice underscore species-specific differences in Aβ clearance and ApoE isoform function.
  • Mouse ApoE limitations in modeling human ApoE biology necessitate humanized models for studying ApoE's role in AD.