Extracellular Proteolysis of Apolipoprotein E (apoE) by Secreted Serine Neuronal Protease
Open accessAbstract
Under normal conditions, brain apolipoprotein E (apoE) is secreted and lipidated by astrocytes, then taken up by neurons via receptor mediated endocytosis. Free apoE is either degraded in intraneuronal lysosomal compartments or released. Here we identified a novel way by which apoE undergoes proteolysis in the extracellular space via a secreted neuronal protease. We show that apoE is cleaved in neuronal conditioned media by a secreted serine protease. This apoE cleavage was inhibited by PMSF and α1-antichymotrypsin, but not neuroserpin-1 or inhibitors of thrombin and cathepsin G, supporting its identity as a chymotrypsin like protease. In addition, apoE incubation with purified chymotrypsin produced a similar pattern of apoE fragments. Analysis of apoE fragments by mass spectrometry showed cleavages occurring at the C-terminal side of apoE tryptophan residues, further supporting our identification of cleavage by chymotrypsin like protease. Hippocampal neurons were more efficient in mediating this apoE cleavage than cortical neurons. Proteolysis of apoE4 generated higher levels of low molecular weight fragments compared to apoE3. Primary glial cultures released an inhibitor of this proteolytic activity. Together, these studies reveal novel mechanism by which apoE can be regulated and therefore could be useful in designing apoE directed AD therapeutic approaches.
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In neurons, ApoE4 undergoes preferential proteolytic cleavage, generating neurotoxic fragments.
“In neuron, ApoE4 undergoes preferential proteolytic cleavage, generating neurotoxic fragments [20].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [20]
The Results report that a protease secreted by hippocampal neurons generates more fragments from apoE4 than apoE3. But the paper locates this cleavage in extracellular conditioned medium, not inside neurons. The Introduction and Discussion describe evidence that apoE fragments can be neurotoxic; this study does not establish that its own fragments are neurotoxic. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA similar proteolyzed form of ApoE has been observed in other brain-derived cell lines.
“A similar proteolyzed form of ApoE has been observed in other brain-derived cell lines.38”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [38]
The Discussion reports ApoE fragments in live hippocampal and cortical neuronal cultures, supporting the observation of proteolyzed ApoE in brain-derived cells. But the Materials and Methods identifies these as primary rat neuronal cultures, not cell lines; the claim’s cell-line specificity is unsupported. No page numbers are available in our copy. (LLM, conf=0.86)
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- Authors
- Tamboli, I. Y., Heo, D., & Rebeck, G. W.
- Affiliations
- Georgetown University (US)
- Corresponding author
- Rebeck, G. William
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-03-27
- Volume
- 9
- Issue
- 3
- Pages
- e93120
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3968057
- OpenAlex
- W2100006021
- Cited by
- 35
- References
- 80
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 6 · 2017: 2 · 2016: 4 · 2015: 5 · 2014: 1
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Johns Hopkins University
- National Institute on Aging (P01AG030128, R01AG035379)
- National Institute on Minority Health and Health Disparities (MD20892)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, extracellular proteolysis, serine protease, chymotrypsin-like protease, APOE ε4, APOE3, hippocampal neurons, cortical neurons, glial cells, Alzheimer's disease
- MeSH terms
- Neuroserpin, alpha 1-Antichymotrypsin, Amino Acid Sequence, Animals, Apolipoproteins E, Brain, Cells, Cultured, Chymotrypsin, Extracellular Space, Humans, Molecular Sequence Data, Neuroglia, Neurons, Neuropeptides, Serpins, Culture Media, Conditioned, Pyramidal Cells, Rats, Apolipoprotein E3, Apolipoprotein E4, Serine Proteases, Proteolysis
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