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Cystatin C-Cathepsin B Axis Regulates Amyloid Beta Levels and Associated Neuronal Deficits in an Animal Model of Alzheimer's Disease
Open accessAbstract
Impaired degradation of amyloid beta (Abeta) peptides could lead to Abeta accumulation, an early trigger of Alzheimer's disease (AD). How Abeta-degrading enzymes are regulated remains largely unknown. Cystatin C (CysC, CST3) is an endogenous inhibitor of cysteine proteases, including cathepsin B (CatB), a recently discovered Abeta-degrading enzyme. A CST3 polymorphism is associated with an increased risk of late-onset sporadic AD. Here, we identified CysC as the key inhibitor of CatB-induced Abeta degradation in vivo. Genetic ablation of CST3 in hAPP-J20 mice significantly lowered soluble Abeta levels, the relative abundance of Abeta1-42, and plaque load. CysC removal also attenuated Abeta-associated cognitive deficits and behavioral abnormalities and restored synaptic plasticity in the hippocampus. Importantly, the beneficial effects of CysC reduction were abolished on a CatB null background, providing direct evidence that CysC regulates soluble Abeta and Abeta-associated neuronal deficits through inhibiting CatB-induced Abeta degradation.
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“while CyC knockout is associated with reduced amyloid burden.94”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [94]
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Metadata
- Authors
- Sun, B., Zhou, Y., Halabisky, B., Lo, I., Cho, S.-H., Mueller-Steiner, S., Devidze, N., Wang, X., Grubb, A., & Gan, L.
- Affiliations
- University of California, San Francisco (US)
- Skåne University Hospital (SE)
- Corresponding author
- Gan, Li
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 60
- Issue
- 2
- Pages
- 247-257
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2755563
- OpenAlex
- W2039502252
- Cited by
- 231
- References
- 55
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 10 · 2023: 17 · 2022: 11 · 2021: 15 · 2020: 9 · 2019: 10 · 2018: 15 · 2017: 21 · 2016: 13 · 2015: 8 · 2014: 15 · 2013: 15 · 2012: 11
- FWCI
- 9.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1750 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Gladstone Institutes
- Vetenskapsrådet
- National Institutes of Health (1c06rr018928-01)
- National Institute on Aging (R21AG024447, AG024447)
- National Center for Research Resources (C06-RR-018928)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- cystatin C, cathepsin B, amyloid-beta, Alzheimer's disease, amyloid beta degradation, cysteine protease inhibition, amyloid plaques, cognitive impairment, synaptic plasticity, hippocampus
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cathepsin B, Peptide Fragments, Polymorphism, Genetic, Amyloid beta-Peptides, Mice, Knockout, Genetic Predisposition to Disease, Mice, Cystatin C, Plaque, Amyloid
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