Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice
Giannisis, Andreas ; Patra, Kalicharan ; Edlund, Anna K LU ; Nieto, Lur Agirrezabala ; Benedicto-Gras, Joan ; Moussaud, Simon ; de la Rosa, Andrés ; Twohig, Daniel LU
; Bengtsson, Tore
and Fu, Yuan
, et al.
(2022)
In Molecular Psychiatry
27(8).
p.3533-3543
- 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 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... (More)
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.
(Less)
- author
- Giannisis, Andreas
; Patra, Kalicharan
; Edlund, Anna K
LU
; Nieto, Lur Agirrezabala
; Benedicto-Gras, Joan
; Moussaud, Simon
; de la Rosa, Andrés
; Twohig, Daniel
LU
; Bengtsson, Tore
and Fu, Yuan
, et al. (More)
- Giannisis, Andreas
; Patra, Kalicharan
; Edlund, Anna K
LU
; Nieto, Lur Agirrezabala
; Benedicto-Gras, Joan
; Moussaud, Simon
; de la Rosa, Andrés
; Twohig, Daniel
LU
; Bengtsson, Tore
; Fu, Yuan
; Bu, Guojun
; Bial, Greg
; Foquet, Lander
; Hammarstedt, Christina
; Strom, Stephen
; Kannisto, Kristina
; Raber, Jacob
; Ellis, Ewa
and Nielsen, Henrietta M
LU
(Less)
- publishing date
- 2022-04-13
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Animals, Mice, Apolipoprotein E4/genetics, Neurodegenerative Diseases, Mice, Inbred NOD, Apolipoproteins E/genetics, Brain/metabolism, Alzheimer Disease/genetics, Genotype, Biomarkers, Liver/metabolism
- in
- Molecular Psychiatry
- volume
- 27
- issue
- 8
- pages
- 11 pages
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85128029153
- pmid:35418601
- ISSN
- 1359-4184
- DOI
- 10.1038/s41380-022-01548-0
- language
- English
- LU publication?
- no
- additional info
- © 2022. The Author(s).
- id
- f1d11875-eb3c-4fe8-9354-ea34d0cd8bc1
- date added to LUP
- 2024-06-10 15:11:53
- date last changed
- 2024-06-25 05:54:59
@article{f1d11875-eb3c-4fe8-9354-ea34d0cd8bc1,
abstract = {{<p>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.</p>}},
author = {{Giannisis, Andreas and Patra, Kalicharan and Edlund, Anna K and Nieto, Lur Agirrezabala and Benedicto-Gras, Joan and Moussaud, Simon and de la Rosa, Andrés and Twohig, Daniel and Bengtsson, Tore and Fu, Yuan and Bu, Guojun and Bial, Greg and Foquet, Lander and Hammarstedt, Christina and Strom, Stephen and Kannisto, Kristina and Raber, Jacob and Ellis, Ewa and Nielsen, Henrietta M}},
issn = {{1359-4184}},
keywords = {{Animals; Mice; Apolipoprotein E4/genetics; Neurodegenerative Diseases; Mice, Inbred NOD; Apolipoproteins E/genetics; Brain/metabolism; Alzheimer Disease/genetics; Genotype; Biomarkers; Liver/metabolism}},
language = {{eng}},
month = {{04}},
number = {{8}},
pages = {{3533--3543}},
publisher = {{Nature Publishing Group}},
series = {{Molecular Psychiatry}},
title = {{Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice}},
url = {{http://dx.doi.org/10.1038/s41380-022-01548-0}},
doi = {{10.1038/s41380-022-01548-0}},
volume = {{27}},
year = {{2022}},
}