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Cited by 139Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

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Huynh, Tien-Phat V., Wang, Chao, Tran, Ainsley C., Tabor, G. Travis, Mahan, Thomas E., Francis, Caroline M., Finn, Mary Beth, Spellman, Rebecca +4 more·2019·Molecular Neurodegeneration
DOI 10.1186/s13024-019-0337-1PMC PMC6796484
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Abstract

Background: The apolipoprotein E ( APOE ) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-β (Aβ) deposition in the brain in the form of both Aβ-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown. Methods: We have begun to address these questions by generating new lines of APOE knock-in ( APOE -KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition. Results: As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE -KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE -KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aβ accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected. Conclusions: Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.

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  • APOE circulating in the blood is predominantly produced by the liver; however, the BBB keeps this pool of peripheral APOE separated from that produced in the CNS.

    “APOE circulating in the blood is predominantly produced by the liver; however, the BBB keeps this pool of peripheral APOE separated from that produced in the CNS181,182.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [181]

  • APOE is not transferred over the blood brain barrier, suggesting astrocytes are the main contributor of APOE in the brain.

    “However, APOE is not transferred over the blood brain barrier (Huynh et al, 2019; Lane-Donovan et al, 2016) suggesting that astrocytes are the main contributor of APOE in the brain (Boyles et al, 1985; Zhang et al, 2014).”

    From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Huynh et al, 2019

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Authors
Huynh, T.-P. V., Wang, C., Tran, A. C., Tabor, G. T., Mahan, T. E., Francis, C. M., Finn, M. B., Spellman, R., Manis, M., Tanzi, R. E., Ulrich, J. D., & Holtzman, D. M.
Affiliations
  • Washington University in St. Louis (US)
  • Harvard University (US)
Corresponding author
Holtzman, David M.
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2019-10-17
Volume
14
Issue
1
Pages
37-37
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-019-0337-1
PMC
PMC6796484
OpenAlex
W2980668035
Cited by
139
References
98
Citations by year
2026: 15 · 2025: 19 · 2024: 27 · 2023: 27 · 2022: 33 · 2021: 9 · 2020: 9
FWCI
8.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Cure Alzheimer's Fund (no number)
  • Howard Hughes Medical Institute (Gilliam Fellowship)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
apolipoprotein E, Alzheimer's disease, amyloid-beta deposition, astrocytes, microglia, hepatocytes, APOE isoforms, APP/PS1 mice, amyloid plaques, cerebral amyloid angiopathy, lipoprotein particles, plasma lipid profile, cell type-specific gene deletion
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Brain, Disease Models, Animal, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Cerebral Amyloid Angiopathy, Microglia, Plaque, Amyloid

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