Related Experiment Videos
ADAM10 and ADAM17 are degraded by lysosomal pathway via asparagine endopeptidase
Xingyu Zhang1, Li Tang1, Zhentao Zhang1
1Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Abstract:
A disintegrin and metalloproteinases 10 (ADAM10) and ADAM17 are transmembrane metalloproteinases that cleave the membrane-anchored proteins. They act as α-secretase that cleaves amyloid precursor protein (APP), precluding the production of amyloid-β, thus protecting against the onset of Alzheimer's disease (AD). However, the degradation pathway of ADAM10 and ADAM17 remains unknown. In this study, we show that ADAM10 and ADAM17 are degraded through the lysosomal pathway. The lysosomal cysteine protease, AEP, plays an important role in the degradation of ADAM10/17. AEP directly cleaves ADAM10/17. Knockout of AEP increases the content of ADAM10/17 in the brain. Given the protective role of ADAM10 and ADAM17 against AD, AEP-mediated degradation of ADAM10/17 may be involved in the pathogenesis of AD.
Insights
The lysosomal protease AEP degrades ADAM10 and ADAM17, enzymes that protect against Alzheimer's disease (AD). AEP-mediated degradation of these enzymes may contribute to AD pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- ADAM10 and ADAM17 are metalloproteinases crucial for cleaving membrane-bound proteins.
- These enzymes act as alpha-secretases, processing amyloid precursor protein (APP) and preventing amyloid-beta production, offering protection against Alzheimer's disease (AD).
- The degradation pathways for ADAM10 and ADAM17 are currently unknown.
Purpose of the Study:
- To elucidate the degradation pathway of ADAM10 and ADAM17.
- To investigate the role of the lysosomal cysteine protease, AEP, in ADAM10/17 degradation.
- To explore the potential link between AEP-mediated degradation and Alzheimer's disease pathogenesis.
Main Methods:
- Investigated the degradation pathway of ADAM10 and ADAM17 using cellular and molecular biology techniques.
- Examined the direct interaction and cleavage activity of AEP on ADAM10/17.
- Utilized knockout models to assess the impact of AEP absence on ADAM10/17 levels in the brain.
Main Results:
- ADAM10 and ADAM17 are degraded via the lysosomal pathway.
- AEP directly cleaves ADAM10 and ADAM17.
- AEP knockout leads to increased levels of ADAM10 and ADAM17 in the brain.
Conclusions:
- The lysosomal cysteine protease AEP plays a significant role in degrading ADAM10 and ADAM17.
- AEP-mediated degradation of ADAM10/17 may be implicated in the pathogenesis of Alzheimer's disease.
- Targeting AEP could offer a novel therapeutic strategy for AD.