Brain integrity is altered by hepatic APOE epsilon 4 in humanized-liver mice

Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer's disease (AD) risk and AD biomarker levels. Carriers of APOE epsilon 4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOE epsilon 4 carriers. Whether altered plasma liver-derived apoE or specifically an APOE epsilon 4 liver phenotype promotes neurodegeneration is unknown. Here we investigated the brains of Fah-/-, Rag2-/-, Il2rg-/- mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE epsilon 4/epsilon 4 versus an APOE epsilon 2/epsilon 3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE epsilon 4/epsilon 4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOE epsilon 4-associated risk of neurodegenerative disease.