Apolipoprotein E isoform mediated regulation of nitric oxide release
Abstract
Progressive dysfunction and death of neurons in Alzheimer's dementia is enhanced in patients carrying one or more APOE4 alleles who also display increased presence of oxidative stress markers. Modulation of oxidative stress is a nontraditional and physiologically relevant immunomodulatory function of apolipoprotein E (apoE). Stimulated peritoneal macrophages from APOE-transgenic replacement (APOE-TR) mice expressing only human apoE3 or human apoE4 protein isoforms were utilized as mouse models to investigate the role of apoE protein isoforms and gender in the regulation of oxidative stress. Macrophages from male APOE4/4-TR mice produced significantly higher levels of nitric oxide than from male APOE3/3-TR mice, while macrophages from female APOE3/3-TR and female APOE4/4-TR mice produced the similar levels of nitric oxide. Primary cultures of microglial cells of APOE4 transgenic mice also produced significantly more nitric oxide than microglia from APOE3 transgenic mice. These data suggest a potentially novel mechanism for gender-dependent and apoE isoform-dependent immune responses that parallel the genetic susceptibility of APOE4 carriers for the development of Alzheimer's disease.
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This study did not address specific functions of microglia or astrocytes, which may also be influenced by sex hormones.
“This study did not address specific functions of microglia or astrocytes, which may also be influenced by sex hormones 9, 13, 14, 19, 26, 40).”
From SJL Mice Exposed to Cuprizone Intoxication Reveal Strain and Gender Pattern Differences in Demyelination (2009) · cites this paper as [9]
APOE4 has been implicated in multiple pathophysiological functions including pro-inflammatory state in microglia and astrocytes, endolysosomal dysfunction, impaired autophagy, inducing and promoting spreading of tau pathology, neurodegeneration, maintaining integrity of pericytes and blood brain barrier, and impaired myelination in oligodendrocytes.
“Indeed, APOE4 has been implicated in the pro-inflammatory state in microglia (Brown et al, 2002; Colton et al, 2005; Lanfranco et al, 2021; Lin et al, 2018; Serrano-Pozo et al, 2021; Vitek et al, 2009) and astrocytes (Arnaud et al, 2022); endolysosomal dysfunction (Ji et al, 2002; Nuriel et al, 2017; Pohlkamp et al, 2021; Prasad and Rao, 2018; Xian et al, 2018); impaired autophagy (Parcon et al, 2”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Brown et al, 2002
Cites
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Self-citationIs the Risk of Developing Alzheimer's Disease Greater for Women than for Men?
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Gender and age modify the association between APOE and AD-related neuropathology
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APOE genotype-specific differences in the innate immune response
Vitek, M. P., Brown, C. M., & Colton, C. A. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.11.014 · Cited by 362 · see citing works
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Apolipoprotein E as a β-amyloid-independent factor in Alzheimer’s disease
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Preman, P., Moechars, D., Fertan, E., Wolfs, L., Serneels, L., Shah, D., Lamote, J., Poovathingal, S., Snellinx, A., Mancuso, R., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00162-7 · Cited by 32 · see citing works
- Authors
- Brown, C. M., Wright, E., Colton, C. A., Sullivan, P. M., Laskowitz, D. T., & Vitek, M. P.
- Affiliations
- Duke University (US)
- Duke Medical Center (US)
- Corresponding author
- Vitek, Michael P.
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 32
- Issue
- 11
- Pages
- 1071-1075
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W1500145074
- Cited by
- 84
- References
- 3
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 2 · 2019: 2 · 2018: 1 · 2016: 2 · 2015: 3 · 2014: 3 · 2013: 4 · 2012: 3
- FWCI
- 2.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- National Institutes of Health (5r01ag015383-02)
- National Institute on Aging (AG15307, P50 AG05128, AG15383, P50AG005128, P50 AG36718)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- apolipoprotein E, APOE ε4, APOE3, nitric oxide, oxidative stress, Alzheimer's disease, macrophages, microglia, sex differences, immune response, neuroinflammation
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Crosses, Genetic, Female, Heterozygote, Homozygote, Humans, Macrophages, Male, Mice, Inbred C57BL, Nitric Oxide, Nitrites, Peritoneum, Microglia, Mice, Knockout, Protein Isoforms, Mice, Apolipoprotein E3, Apolipoprotein E4
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