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.