TY - JOUR
T1 - Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice
AU - Giannisis, Andreas
AU - Patra, Kalicharan
AU - Edlund, Anna K.
AU - Nieto, Lur Agirrezabala
AU - Benedicto-Gras, Joan
AU - Moussaud, Simon
AU - de la Rosa, Andrés
AU - Twohig, Daniel
AU - Bengtsson, Tore
AU - Fu, Yuan
AU - Bu, Guojun
AU - Bial, Greg
AU - Foquet, Lander
AU - Hammarstedt, Christina
AU - Strom, Stephen
AU - Kannisto, Kristina
AU - Raber, Jacob
AU - Ellis, Ewa
AU - Nielsen, Henrietta M.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
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U2 - 10.1038/s41380-022-01548-0
DO - 10.1038/s41380-022-01548-0
M3 - Article
C2 - 35418601
AN - SCOPUS:85128029153
SN - 1359-4184
VL - 27
SP - 3533
EP - 3543
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 8
ER -