Matrix Metalloproteinases Expressed by Astrocytes Mediate Extracellular Amyloid-β Peptide Catabolism
Open accessAbstract
It has been postulated that the development of amyloid plaques in Alzheimer's disease (AD) may result from an imbalance between the generation and clearance of the amyloid-β peptide (Aβ). Although familial AD appears to be caused by Aβ overproduction, sporadic AD (the most prevalent form) may result from impairment in clearance. Recent evidence suggests that several proteases may contribute to the degradation of Aβ. Furthermore, astrocytes have recently been implicated as a potential cellular mediator of Aβ degradation. In this study, we examined the possibility that matrix metalloproteinases (MMPs), proteases known to be expressed and secreted by astrocytes, could play a role in extracellular Aβ degradation. We found that astrocytes surrounding amyloid plaques showed enhanced expression of MMP-2 and MMP-9 in aged amyloid precursor protein (APP)/presenilin 1 mice. Moreover, astrocyte-conditioned medium (ACM) degraded Aβ, lowering levels and producing several fragments after incubation with synthetic human Aβ 1–40 and Aβ 1–42 . This activity was attenuated with specific inhibitors of MMP-2 and -9, as well as in ACM derived from mmp-2 or -9 knock-out (KO) mice. In vivo , significant increases in the steady-state levels of Aβ were found in the brains of mmp-2 and -9 KO mice compared with wild-type controls. Furthermore, pharmacological inhibition of the MMPs with N -[(2 R )-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]- l -tryptophan methylamide (GM 6001) increased brain interstitial fluid Aβ levels and elimination of half-life in APPsw mice. These results suggest that MMP-2 and -9 may contribute to extracellular brain Aβ clearance by promoting Aβ catabolism.
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Expression of MMP-9 is up-regulated in reactive astrocytes surrounding plaques.
“We have previously found that the expression of MMP-9 is up-regulated in reactive astrocytes surrounding plaques (61, 62)”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [62]
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- Authors
- Yin, K.-J., Cirrito, J. R., Yan, P., Hu, X., Xiao, Q., Pan, X., Bateman, R., Song, H., Hsu, F.-F., Turk, J., Xu, J., Hsu, C. Y., Mills, J. C., Holtzman, D. M., & Lee, J.-M.
- Affiliations
- Washington University in St. Louis (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-10-25
- Volume
- 26
- Issue
- 43
- Pages
- 10939-10948
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6674654
- OpenAlex
- W2011574003
- Cited by
- 381
- References
- 7
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 15 · 2023: 22 · 2022: 18 · 2021: 27 · 2020: 34 · 2019: 16 · 2018: 18 · 2017: 20 · 2016: 17 · 2015: 29 · 2014: 21 · 2013: 14 · 2012: 20
- FWCI
- 8.64
- 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)
- Funders
- American Heart Association (0630209N)
- National Institutes of Health (5p60dk020579-35, 5p41rr000954-34, DK20579, P60-DK-20579, DK56341, P41 RR00954, AG13956)
- U.S. Public Health Service (P60-DK-20579, P41‐RR‐00954, P30‐DK‐56341)
- National Institute on Aging (R01AG013956, R37AG013956, AG13956)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60-DK20579, P30-DK56341, P60-DK-020579, P30DK056341)
- National Institute of Neurological Disorders and Stroke (R01NS040525, NS 40525, NS48283, R01NS048283)
- National Center for Research Resources (P41-RR000954, P41 RR-00954)
- 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
- matrix metalloproteinases, MMP-2, MMP-9, astrocytes, amyloid-beta, amyloid-beta clearance, Alzheimer's disease, amyloid plaques, GM6001, protease inhibitors, extracellular proteolysis, brain interstitial fluid
- MeSH terms
- Animals, Astrocytes, Cells, Cultured, HeLa Cells, Humans, Mice, Inbred C57BL, Mice, Transgenic, Gene Expression Regulation, Enzymologic, Amyloid beta-Peptides, Mice, Knockout, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Protein Transport, Extracellular Fluid, Mice
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