Cited by 231Alzheimer's disease research and treatmentsProtease and Inhibitor MechanismsDementia and Cognitive Impairment Research

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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Sun, Binggui, Zhou, Yungui, Halabisky, Brian, Lo, Iris, Cho, Seo-Hyun, Mueller-Steiner, Sarah, Devidze, Nino, Wang, Xin +2 more·2008·Neuron

Abstract

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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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)
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
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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