Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E
Abstract
A role for beta-amyloid precursor protein (beta-APP) in the development of Alzheimer's disease has been indicated by genetics, and many conditions in which beta-APP is raised have been associated with an increased risk of Alzheimer's disease or an Alzheimer's-like pathology. Inflammatory events may also contribute to Alzheimer's disease. Here we investigate whether a secreted derivative of beta-APP (sAPP-alpha) can induce inflammatory reactions in microglia, which are brain cells of monocytic lineage. We found that treatment with sAPP-alpha increased markers of activation in microglia and enhanced their production of neurotoxins. The ability of sAPP-alpha to activate microglia was blocked by prior incubation of the protein with apolipoprotein E3 but not apolipoprotein E4, a variant associated with an increased risk for Alzheimer's. A product of amyloidogenic beta-APP processing (sAPP-beta) also activated microglia. Because sAPP-beta is deficient in the neuroprotective activity shown by sAPP-alpha, our results indicate that increased amyloidogenic processing could adversely affect the balance of sAPP activities that determine neuronal viability.
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Exogenously applied apoE4 has more robust pro-inflammatory activity than apoE3 in astrocytes and microglial cells.
“In support of this hypothesis, several studies demonstrated that exogenously applied apoE4 has more robust pro-inflammatory activity than apoE3 in astrocytes and microglial cells (Barger and Harmon, 1997; Guo et al., 2004).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Barger and Harmon, 1997
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- Authors
- Barger, S. W., & Harmon, A. D.
- Affiliations
- University of Arkansas for Medical Sciences (US)
- John L. McClellan Memorial Veterans Hospital (US)
- Corresponding author
- Barger, Steven W.
- ORCID
- Barger, Steven W.
- Venue
- Nature
- Published
- 1997-08-28
- Volume
- 388
- Issue
- 6645
- Pages
- 878-881
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1657989568
- Cited by
- 622
- References
- 1
- Citations by year
- 2026: 13 · 2025: 6 · 2024: 12 · 2023: 21 · 2022: 15 · 2021: 20 · 2020: 18 · 2019: 19 · 2018: 18 · 2017: 12 · 2016: 20 · 2015: 27 · 2014: 18 · 2013: 13 · 2012: 27
- FWCI
- 19.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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
- microglial activation, Alzheimer's disease, amyloid precursor protein, apolipoprotein E, APOE ε4, neuroinflammation, neurotoxicity, amyloidogenic processing, neuroprotection, neuronal viability
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Cell Line, Gene Expression Regulation, Humans, Inflammation, Interleukin-1, Peptide Fragments, NF-kappa B, Amyloid beta-Protein Precursor, Cell Death, Microglia, Nitric Oxide Synthase, Rats
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