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APOE Genotype Differentially Modulates Prion Pathology in a Mouse Model

ABSTRACT: Background: APOE polymorphism affects the risk of occurrence and the rate of progression in several neurodegenerative diseases including late-onset Alzheimer’s disease, primary tauopathies, α-synucleinopathy, and age-related macular degeneration, but its role in prion pathogenesis remains unestablished. Using APOE targeted replacement (TR) mice, we investigated how APOE genotype affects key neurodegenerative mechanisms involved in prion pathology. Methods: Male and female ε2/ε2, ε3/ε3, and ε4/ε4 APOE-TR mice were inoculated with 22L mouse adapted scrapie strain or normal brain homogenate and followed using serial behavioral testing from 10-week post inoculation (wpi.) onward. Mice were euthanized at 23 wpi. when all prion-infected animals were visibly symptomatic. Multiple neuropathological, biochemical, and transcriptomic metrics were analyzed and compared across animals of different APOE genotypes. Results: ε4/ε422L mice featured the shortest disease latency time, the worst neurological score at the end of the study, and the highest load of spongiform lesions. ε2/ε222L mice performed significantly better compared to ε4/ε422L mice but also significantly worse than ε3/ε322L animals. Numerous aspects of PrP proteinopathy were exacerbated in the presence of the ε4 allele including increased PrPSc accumulation, reduced PrP solubility, and increased PrP oligomerization. These metrics were comparable between ε2/ε222L and ε3/ε322L mice. Prion pathology significantly increased brain apolipoprotein (apo) E levels, with the greatest increase in ε4/ε422L mice. All apoE isoforms formed complexes with conformationally altered PrP, but in ε4/ε422L mice the PrP/apoE interaction was the strongest. The load of reactive microglia and astrocytes, transcriptomic markers representative of neurodegenerative microglia and chronically reactive astrocytes were the highest in ε4/ε422L mice, but they also were significantly upregulated in ε2/ε222L mice compared to ε3/ε322L animals. Conclusions: APOE polymorphism differentially regulates the progression of prion pathology. We identified two mechanisms attributable to the detrimental effect endowed by the ε4 allele: the increased conversion and accumulation of the PrPSc conformer, and the worsening of prion-associated neuroinflammation. Although less severe than ε4, the ε2 allele also is associated with an increased inflammatory response, rendering disease outcome worse compared to the ε3 allele. Findings of this animal model study suggest both ε4 and ε2 alleles are disadvantageous determinants in prion pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE307182 | GEO | 2025/12/31

REPOSITORIES: GEO

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APOE Genotype Differentially Modulates Prion Pathology in a Mouse Model

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