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Basic Science and Pathogenesis.

Hirra A Arain1,2,3, Jason A Mares2,3, Anurag Sharma2,3

  • 1Department of Cell Biology and Pathology, New York, NY, USA.

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Summary
This summary is machine-generated.

The apolipoprotein E e4 (APOE4) allele influences Alzheimer's disease (AD) progression. This study developed a novel APOE-tau mouse model, revealing that APOE genotype, sex, and age significantly alter tau pathology spread in the brain.

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Area of Science:

  • Neuroscience
  • Genetics
  • Pathology

Background:

  • The apolipoprotein E e4 (APOE4) allele is the primary genetic risk factor for sporadic Alzheimer's disease (AD).
  • APOE4's role in modulating tau tangle pathogenesis, particularly in a localized manner consistent with AD pathology, requires further investigation.

Purpose of the Study:

  • To develop and characterize a novel humanized APOE-tau mouse model that replicates region-specific tau propagation observed in early AD.
  • To investigate the influence of APOE genotype, sex, and age on tau pathology, neurodegeneration, and spatial memory.

Main Methods:

  • Developed a novel humanized APOE mouse model by crossing homozygous humanized APOE (APOE3/3 and APOE4/4) mice with EC-Tau mice.
  • Analyzed male and female mice at three-time points (5-7, 15-17, and 25-27 months) using in-vivo and ex-vivo techniques.
  • Assessed tau pathology, neurodegeneration, and spatial memory, alongside spatial transcriptomics analysis.

Main Results:

  • Observed differential tau spread and neurodegeneration influenced by APOE genotype in a sex- and age-dependent manner.
  • Homozygous APOE4 mice exhibited decreased tau pathology in early AD-associated regions, particularly female mice showing reduced tau propagation and hippocampal atrophy.
  • Spatial transcriptomics revealed significant alterations in genes related to neuronal and glia homeostasis in APOE4 mice.

Conclusions:

  • Generated and characterized a novel APOE-tau mouse model that accurately replicates region-specific tau propagation in early AD.
  • Provided novel insights into how APOE genotype, sex, and age interact to modulate pathological tau propagation in vulnerable brain regions.
  • Highlighted the complex interplay between genetic factors, sex, and age in Alzheimer's disease pathogenesis.