Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice

Andreas Giannisis, Kalicharan Patra, Anna K. Edlund, Lur Agirrezabala Nieto, Joan Benedicto-Gras, Simon Moussaud, Andrés de la Rosa, Daniel Twohig, Tore Bengtsson, Yuan Fu, Guojun Bu, Greg Bial, Lander Foquet, Christina Hammarstedt, Stephen Strom, Kristina Kannisto, Jacob Raber, Ewa Ellis, Henrietta M. Nielsen

Research output: Contribution to journalArticlepeer-review


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 APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 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 ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 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 APOEε4-associated risk of neurodegenerative disease.

Original languageEnglish (US)
Pages (from-to)3533-3543
Number of pages11
JournalMolecular Psychiatry
Issue number8
StatePublished - Aug 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience


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