Cystatin C-Cathepsin B Axis Regulates Amyloid Beta Levels and Associated Neuronal Deficits in an Animal Model of Alzheimer's Disease
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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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CyC knockout is associated with reduced amyloid burden.
“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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- 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
- 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 › 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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