ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

P301S/E4 mice exhibit significantly higher tau levels in the brain at three months of age compared to other genotypes.

• ApoE4 is associated with increased tau levels and somatodendritic tau redistribution in transgenic mice.
• Distinct patterns of phosphorylated tau protein staining are observed in mice with different ApoE genotypes by nine months of age.
• P301S/E4 mice develop more brain atrophy and neuroinflammation than those with E2 or E3 genotypes, while ApoE knockout mice show protection from these changes.
• E4-expressing microglia demonstrate heightened immune reactivity and, when co-cultured with tau-expressing neurons, lead to increased secretion of tumour-necrosis factor-α and reduced neuronal viability.
• In sporadic primary tauopathy, the presence of an ε4 allele correlates with more severe neurodegeneration, and ε4-carriers with amyloid-β pathology experience faster disease progression.
• The findings suggest that ApoE influences tau pathology and neurodegeneration independently of amyloid-β.

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