A Free Radical-Generating System Regulates Amyloid Oligomers: Involvement of Cathepsin B
Patricia Llorente1,2, Henrike Kristen1,2, Isabel Sastre1,2,3
1Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, Madrid, Spain.
Abstract:
Amyloid-β (Aβ), a major component of senile plaques, is generated via the proteolysis of amyloid-β protein precursor (AβPP). This cleavage also produces AβPP fragment-derived oligomers which can be highly neurotoxic. AβPP metabolism/processing is affected by many factors, one of which is oxidative stress (OS). Associated with aging, OS is an important risk factor for Alzheimer's disease. In addition, the protein degradation systems, especially those involving cathepsins, are impaired in aging brains. Moreover, cathepsin B (CTSB) is a cysteine protease with potentially specific roles in AβPP proteolysis (β-secretase activity) and Aβ clearance (Aβ degradative activity). The present work examines the effect of OS and the involvement of CTSB in amyloid oligomer formation. The xanthine/xanthine oxidase (X-XOD) free radical generating system induced the partial inhibition of CTSB activity, which was accompanied by an increase in large amyloid oligomers. These were located throughout the cytosol and in endo-lysosomal vesicles. Cells treated with the CTSB inhibitor CA-074Me also showed increased amyloid oligomer levels, whereas those subjected to OS in the presence of the inhibitor showed no such increase. However, CTSB inhibition clearly modulated the AβPP metabolism/processing induced by X-XOD, as revealed by the increase in intracellular AβPP and secreted α-secretase-cleaved soluble AβPP. The present results suggest that CTSB participates in the changes of amyloid oligomer induced by mild OS.
Insights
Oxidative stress increases neurotoxic amyloid oligomers by inhibiting cathepsin B (CTSB). CTSB activity is crucial for regulating amyloid-beta protein precursor (AβPP) processing and amyloid oligomer formation, particularly under oxidative stress conditions.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Amyloid-beta (Aβ) oligomers are neurotoxic and linked to Alzheimer's disease.
- Oxidative stress (OS) and impaired protein degradation, including cathepsins, are associated with aging and Alzheimer's.
- Cathepsin B (CTSB) plays a role in AβPP processing and Aβ clearance.
Purpose of the Study:
- To investigate the effect of OS on amyloid oligomer formation.
- To determine the involvement of CTSB in OS-induced changes in amyloid oligomers.
- To examine how CTSB activity influences AβPP metabolism under OS.
Main Methods:
- Utilized a xanthine/xanthine oxidase (X-XOD) system to induce OS and inhibit CTSB activity.
- Administered a CTSB-specific inhibitor (CA-074Me) to cells.
- Analyzed amyloid oligomer levels, localization, AβPP intracellular levels, and secreted soluble AβPP.
Main Results:
- X-XOD-induced OS partially inhibited CTSB activity, leading to increased large amyloid oligomers in the cytosol and endo-lysosomal vesicles.
- CTSB inhibition alone increased amyloid oligomer levels.
- Inhibition of CTSB prevented OS-induced increases in amyloid oligomers but modulated AβPP processing, increasing intracellular AβPP and secreted α-secretase-cleaved soluble AβPP.
Conclusions:
- CTSB activity is involved in regulating amyloid oligomer formation under mild OS conditions.
- CTSB plays a significant role in modulating AβPP processing influenced by OS.
- Targeting CTSB may offer a therapeutic strategy for managing amyloid pathology in aging and Alzheimer's disease.
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