Brain integrity is altered by hepatic <i>APOE</i> ε4 in humanized-liver mice

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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 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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Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

E H Corder, A M Saunders, W J Strittmatter … (1993)

The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.

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Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy.

Chia-Chen Liu, Chia-Chan Liu, Takahisa Kanekiyo … (2013)

Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E-lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting Apo-E.

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Alzheimer's disease is a synaptic failure.

D. Selkoe (2002)

In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid beta protein.

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Author and article information

Contributors

Henrietta M. Nielsen: henrietta.nielsen@dbb.su.se

Journal

Journal ID (nlm-ta): Mol Psychiatry

Journal ID (iso-abbrev): Mol Psychiatry

Title: Molecular Psychiatry

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1359-4184

ISSN (Electronic): 1476-5578

Publication date (Electronic): 13 April 2022

Publication date PMC-release: 13 April 2022

Publication date (Print): 2022

Volume: 27

Issue: 8

Pages: 3533-3543

Affiliations

[1 ]GRID grid.10548.38, ISNI 0000 0004 1936 9377, Department of Biochemistry and Biophysics, , Stockholm University, ; Stockholm, 10691 Sweden

[2 ]GRID grid.10548.38, ISNI 0000 0004 1936 9377, Department of Molecular Biosciences, , The Wenner-Gren Institute, ; Stockholm, 10691 Sweden

[3 ]GRID grid.417467.7, ISNI 0000 0004 0443 9942, Department of Neuroscience, , Mayo Clinic College of Medicine, ; Jacksonville, FL 32224 USA

[4 ]GRID grid.422900.d, Yecuris Corporation, ; Tualatin, OR 97062 USA

[5 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Laboratory Medicine (LABMED), , Karolinska Institutet, ; Stockholm, 17177 Sweden

[6 ]GRID grid.5288.7, ISNI 0000 0000 9758 5690, Departments of Behavioral Neuroscience, Neurology, and Radiation Medicine, and Division of Neuroscience, ONPPRC, , Oregon Health & Science University, ; Portland, OR 97239 USA

[7 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Clinical Science, Intervention and Technology, (CLINTEC), Division of Transplantation surgery, , Karolinska Institutet, ; Huddinge, 14152 Sweden

Author information

Andreas Giannisis http://orcid.org/0000-0002-3031-5746

Daniel Twohig http://orcid.org/0000-0002-3649-1281

Guojun Bu http://orcid.org/0000-0003-3491-1016

Jacob Raber http://orcid.org/0000-0002-9861-9893

Ewa Ellis http://orcid.org/0000-0002-3057-5337

Article

Publisher ID: 1548

DOI: 10.1038/s41380-022-01548-0

PMC ID: 9708568

PubMed ID: 35418601

SO-VID: fd508734-43cc-4b6f-9891-00dfbc81be72

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 28 February 2021

Date revision received : 21 March 2022

Date accepted : 23 March 2022

Funding

Funded by: FundRef https://doi.org/10.13039/501100004200, Stiftelsen Olle Engkvist Byggmästare;

Award ID: 189-0291

Award ID: 203-0053

Award Recipient : Henrietta M. Nielsen

Funded by: FundRef https://doi.org/10.13039/100006312, BrightFocus Foundation (BrightFocus);

Award ID: A2019446S

Award Recipient : Lander Foquet Jacob Raber Henrietta M. Nielsen

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ScienceOpen disciplines: Molecular medicine

Keywords: neuroscience,molecular biology

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ScienceOpen disciplines: Molecular medicine

Keywords: neuroscience, molecular biology

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

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Most cited references 70

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy.

Alzheimer's disease is a synaptic failure.

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