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Cited by 80Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Cellular Source of Apolipoprotein E4 Determines Neuronal Susceptibility to Excitotoxic Injury in Transgenic Mice

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Buttini, Manuel, Masliah, Eliezer, Yu, Gui-Qiu, Palop, Jorge J., Chang, Shengjun, Bernardo, Aubrey, Lin, Carol, Wyss-Coray, Tony +2 more·2010·The American Journal of Pathology
DOI 10.2353/ajpath.2010.090973PMC PMC2913361
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Abstract

The lipid transport protein apolipoprotein E (apoE) is abundantly expressed in the brain. Its main isoforms in humans are apoE2, apoE3, and apoE4. ApoE4 is the major known genetic risk factor for Alzheimer's disease and also contributes to the pathogenesis of various other neurological conditions. In the central nervous system, apoE is synthesized by glial cells and neurons, but it is unclear whether the cellular source affects its biological activities. To address this issue, we induced excitotoxic injury by systemic kainic acid injection in transgenic Apoe knockout mice expressing human apoE isoforms in astrocytes or neurons. Regardless of its cellular source, apoE3 expression protected neuronal synapses and dendrites against the excitotoxicity seen in apoE-deficient mice. Astrocyte-derived apoE4, which has previously been shown to have detrimental effects in vitro, was as excitoprotective as apoE3 in vivo. In contrast, neuronal expression of apoE4 was not protective and resulted in loss of cortical neurons after excitotoxic challenge, indicating that neuronal apoE4 promotes excitotoxic cell death. Thus, an imbalance between astrocytic (excitoprotective) and neuronal (neurotoxic) apoE4 expression may increase susceptibility to diverse neurological diseases involving excitotoxic mechanisms.

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  • APOE3 from both astrocytes and neurons can protect against neuronal hyperexcitability, whereas neuron-derived (but not astrocyte-derived) APOE4 is detrimental.

    “Mouse models expressing APOE3 or APOE4 exclusively in either astrocytes or neurons (Box 3) show that APOE3 from both cell types can protect against neuronal hyperexcitability, whereas neuron-derived (but not astrocyte-derived) APOE4 is detrimental159,160.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [159]

    The Discussion and Figure 3 (p. 569) support the cell-source distinction for excitotoxic injury: apoE3 from either cell type was protective, while neuron-derived apoE4 increased vulnerability and astrocyte-derived apoE4 was protective. They do not establish protection against neuronal hyperexcitability itself. The Kainic Acid Treatment and Tissue Preparation section says seizure onset, intensity, and duration were comparable across genotypes. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Buttini, M., Masliah, E., Yu, G.-Q., Palop, J. J., Chang, S., Bernardo, A., Lin, C., Wyss-Coray, T., Huang, Y., & Mucke, L.
Affiliations
  • Gladstone Institutes (US)
  • University of California San Diego (US)
  • University of California, San Francisco (US)
Corresponding author
  • Buttini, Manuel
  • Mucke, Lennart
ORCID
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2010-08
Volume
177
Issue
2
Pages
563-569
ISSN
0002-9440 (ISSN-L)
DOI
10.2353/ajpath.2010.090973
PMC
PMC2913361
OpenAlex
W2144405089
Cited by
80
References
8
Citations by year
2026: 3 · 2025: 3 · 2024: 12 · 2023: 3 · 2022: 6 · 2021: 5 · 2020: 3 · 2019: 10 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 5 · 2013: 9 · 2012: 2
FWCI
4.06
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (AG011385, AG022074, NS041787)
  • Merck
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
APOE ε4, apolipoprotein E isoforms, excitotoxicity, astrocytes, neurons, kainic acid, cortical neurons, ApoE-deficient mice, Alzheimer's disease risk
MeSH terms
Animals, Brain, Humans, Kainic Acid, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Excitatory Amino Acid Agonists, Protein Isoforms, Mice, Apolipoprotein E4

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