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Cited by 168Alzheimer's disease research and treatmentsBarrier Structure and Function StudiesNeuroinflammation and Neurodegeneration Mechanisms

Peripheral apoE4 enhances Alzheimer’s pathology and impairs cognition by compromising cerebrovascular function

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Liu, Chia-Chen, Zhao, Jing, Fu, Yuan, Inoue, Yasuteru, Ren, Yingxue, Chen, Yuanxin, Doss, Sydney V., Shue, Francis +32 more·2022·Nature Neuroscience
DOI 10.1038/s41593-022-01127-0PMC PMC10009873
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Abstract

The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer's disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood-brain barrier, differentially impact Alzheimer's disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer's disease.

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  • APOE4 alters blood-brain barrier integrity, influencing metabolite exchange between the periphery and CNS, including reduced brain glucose and lipid transport.

    “APOE4 alters the integrity of the blood brain barrier (BBB) influencing metabolite exchange between the periphery and the central nervous system (CNS) including reduced brain glucose and lipid transport [17][18][19] .”

    From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [18]

    The Results section (“Peripheral apoE4 impairs cerebrovascular functions”; page unavailable) reports increased BBB leakage and reduced tight-junction markers in mice expressing liver-derived apoE4. This supports altered barrier integrity and movement of blood-derived proteins into the brain. The paper does not establish reduced transport of glucose or lipids into the brain; its discussion of metabolism and lipid-related genes does not measure that transport. (LLM, conf=0.88)

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Cited by

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Authors
Liu, C.-C., Zhao, J., Fu, Y., Inoue, Y., Ren, Y., Chen, Y., Doss, S. V., Shue, F., Jeevaratnam, S., Bastea, L., Wang, N., Martens, Y. A., Qiao, W., Wang, M., Zhao, N., Jia, L., Yamazaki, Y., Yamazaki, A., Rosenberg, C. L., Wang, Z., Kong, D., Li, Z., Kuchenbecker, L. A., Trottier, Z. A., Felton, L., Rogers, J., Quicksall, Z. S., Linares, C., Knight, J., Chen, Y., Kurti, A., Kanekiyo, T., Fryer, J. D., Asmann, Y. W., Storz, P., Wang, X., Peng, J., Zhang, B., Kim, B. Y. S., & Bu, G.
Affiliations
  • Mayo Clinic in Florida (US)
  • Mayo Clinic (US)
  • St. Jude Children's Research Hospital (US)
  • University of North Dakota (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • The University of Texas MD Anderson Cancer Center (US)
Corresponding author
  • Liu, Chia-Chen
  • Bu, Guojun
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2022-08
Volume
25
Issue
8
Pages
1020-1033
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-022-01127-0
PMC
PMC10009873
OpenAlex
W4289261776
Cited by
168
References
28
Citations by year
2026: 38 · 2025: 37 · 2024: 45 · 2023: 42 · 2022: 6
FWCI
19.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • National Institutes of Health (1rf1ag062110-01)
  • National Institute on Aging (R21AG057981, RF1AG051504, R37AG027924, U01AG046170, RF1AG054014, RF1AG057181, RF1 AG062110, RF1AG046205, R01AG046205, U01AG052411, U19AG069701)
  • National Cancer Institute (P30CA016672)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E, APOE ε4, Alzheimer's disease, cerebrovascular function, blood-brain barrier, plasma proteome, synaptic plasticity, cognition, amyloid pathology, endothelial integrity, lipoprotein metabolism, complement activation, plasma transfusion, induced pluripotent stem cell-derived endothelial cells, conditional mouse model
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Brain, Cognition, Humans, Mice, Transgenic, Protein Isoforms, Mice, Apolipoprotein E3, Apolipoprotein E4, Induced Pluripotent Stem Cells

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