The Metalloprotease Inhibitor TIMP-3 Regulates Amyloid Precursor Protein and Apolipoprotein E Receptor Proteolysis
Open accessAbstract
Cellular cholesterol levels alter the processing of the amyloid precursor protein (APP) to produce Aβ. Activation of liver X receptors (LXRs), one cellular mechanism to regulate cholesterol homeostasis, has been found to alter Aβ levels in vitro and in vivo . To identify genes regulated by LXR, we treated human neuroblastoma cells with an LXR agonist (TO-901317) and examined gene expression by microarray. As expected, TO-901317 upregulated several cholesterol metabolism genes, but it also decreased expression of a metalloprotease inhibitor, TIMP-3. We confirmed this finding using real-time PCR and by measuring TIMP-3 protein in glia, SY5Y cells, and COS7 cells. TIMP-3 is a member of a family of metalloproteinase inhibitors and blocks A disintegrin and metalloproteinase-10 (ADAM-10) and ADAM-17, two APP α-secretases. We found that TIMP-3 inhibited α-secretase cleavage of APP and an apolipoprotein E (apoE) receptor, ApoER2. TIMP-3 decreased surface levels of ADAM-10, APP, and ApoER2. These changes were accompanied by increased APP β-C-terminal fragment and Aβ production. These data suggest that TIMP-3 preferentially routes APP and ApoER2 away from the cell surface and α-secretase cleavage and encourages endocytosis and β-secretase cleavage. In vivo , TO-901317 decreased brain TIMP-3 levels. TIMP-3 protein levels were increased in human Alzheimer's disease (AD) brain and in APP transgenic mice, suggesting that increased levels of TIMP-3 in AD may contribute to higher levels of Aβ.
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TIMP3 decreases the levels of the soluble extracellular fragment and CTF of ApoER2, suggesting an active role of α-secretase in the first step of ApoER2 processing at the plasma membrane.
“On the other hand, the α-secretase protein inhibitor TIMP3 also decreases the levels of the soluble extracellular fragment and CTF of ApoER2, suggesting an active role of α-secretase in the first step of ApoER2 processing at the plasma membrane [41].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [41]
The α-secretase inhibitor TIMP3 decreases the processing of ApoER2, and α-secretase activity is present at the plasma membrane.
“In addition, the α-secretase inhibitor TIMP3 decreases the processing of ApoER2 [41], and there is evidence indicating that the activity of α-secretase is present at the plasma membrane [67].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [41]
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- Authors
- Hoe, H.-S., Cooper, M. J., Burns, M. P., Lewis, P. A., van der Brug, M., Chakraborty, G., Cartagena, C. M., Pak, D. T. S., Cookson, M. R., & Rebeck, G. W.
- Affiliations
- Georgetown University Medical Center (US)
- Georgetown University (US)
- National Institutes of Health (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-10-03
- Volume
- 27
- Issue
- 40
- Pages
- 10895-10905
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6672812
- OpenAlex
- W1996720919
- Cited by
- 90
- References
- 5
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 10 · 2022: 6 · 2021: 1 · 2020: 12 · 2019: 4 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 1 · 2014: 7 · 2013: 4 · 2012: 5
- FWCI
- 3.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Georgetown University
- National Institutes of Health (AG14473)
- National Institute on Aging (AG14473, R29AG014473, R01AG014473)
- National Institute of Neurological Disorders and Stroke (R01NS048085)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- TIMP-3, amyloid precursor protein, ApoER2, ADAM10, ADAM17, amyloid-beta production, liver X receptor, cholesterol homeostasis, metalloproteinase inhibitors, Alzheimer's disease, APP transgenic mice, endocytosis, gene expression regulation
- MeSH terms
- Liver X Receptors, ADAM10 Protein, Animals, Astrocytes, Cells, Cultured, Chlorocebus aethiops, Cerebral Cortex, DNA-Binding Proteins, Dose-Response Relationship, Drug, Embryo, Mammalian, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Hippocampus, Humans, Membrane Proteins, Neuroblastoma, Neurons, Transfection, Amyloid beta-Protein Precursor, Receptors, Cytoplasmic and Nuclear, Tissue Inhibitor of Metalloproteinase-3, Protein Transport, Low Density Lipoprotein Receptor-Related Protein-1, RNA, Small Interfering, Mice, Rats, ADAM Proteins, Amyloid Precursor Protein Secretases, Orphan Nuclear Receptors
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