학술논문
Brain integrity is altered by hepatic APOEε4 in humanized-liver mice
Document Type
Article
Author
Giannisis, Andreas; Patra, Kalicharan; Edlund, Anna K.; Nieto, Lur Agirrezabala; Benedicto-Gras, Joan; Moussaud, Simon; de la Rosa, Andrés; Twohig, Daniel; Bengtsson, Tore; Fu, Yuan; Bu, Guojun; Bial, Greg; Foquet, Lander; Hammarstedt, Christina; Strom, Stephen; Kannisto, Kristina; Raber, Jacob; Ellis, Ewa; Nielsen, Henrietta M.
Source
Molecular Psychiatry; August 2022, Vol. 27 Issue: 8 p3533-3543, 11p
Subject
Language
ISSN
13594184; 14765578
Abstract
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 APOEε4/ε4 versus an APOEε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOEε4/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.