Related Experiment Videos
A secreted form of human ADAM9 has an alpha-secretase activity for APP
Nika Hotoda1, Hisashi Koike, Noboru Sasagawa
1Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.
Abstract:
ADAM9 (MDC9, meltrin gamma) is a member of the ADAM family of metalloproteases, which play important roles in cell-cell fusion, intracellular signaling, and other cellular functions. Here we cloned a novel form of human ADAM9, designated hADAM9s (s for short), which lacks the carboxyl-terminus. Human ADAM9s was found to be secreted from transfected COS cells. RT-PCR analysis demonstrated that the mRNA for hADAM9s is expressed in human brain, liver, heart, kidney, lung, and trachea. When hADAM9s was co-expressed in COS cells with APP and treated with phorbol ester, the APP was digested exclusively at the alpha-secretory site. These results suggest that hADAM9s has an alpha-secretase-like activity for APP. Non-amyloidgenic cleavage of APP may occur at the plasma membrane. Our new results support a new therapeutic strategy to decrease in the Abeta content by directly activating ADAM9 in the extracellular space.
Insights
A novel short form of ADAM9 (hADAM9s) was identified and found to possess alpha-secretase-like activity. This discovery suggests a new therapeutic strategy for reducing amyloid-beta peptide levels by activating extracellular ADAM9.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- ADAM9 (ADAM metallopeptidase domain 9) is a metalloprotease involved in cellular functions.
- The ADAM family plays roles in cell-cell fusion and intracellular signaling.
Purpose of the Study:
- To clone and characterize a novel, shorter form of human ADAM9 (hADAM9s).
- To investigate the enzymatic activity and potential therapeutic applications of hADAM9s, particularly concerning amyloid precursor protein (APP) processing.
Main Methods:
- Cloning of the novel hADAM9s variant.
- Expression of hADAM9s in transfected COS cells and detection of its secretion.
- RT-PCR analysis to determine hADAM9s mRNA expression in various human tissues.
- Co-expression of hADAM9s with APP in COS cells, followed by phorbol ester treatment to assess APP cleavage.
Main Results:
- A novel secreted form of human ADAM9, hADAM9s, was successfully cloned and expressed.
- hADAM9s mRNA was detected in multiple human tissues, including brain and liver.
- hADAM9s demonstrated exclusive cleavage of APP at the alpha-secretory site, indicating alpha-secretase-like activity.
- This cleavage occurs at the plasma membrane, suggesting a non-amyloidogenic pathway for APP processing.
Conclusions:
- hADAM9s exhibits alpha-secretase-like activity, cleaving APP at the non-amyloidogenic site.
- Extracellular activation of ADAM9 presents a potential therapeutic strategy to reduce amyloid-beta (Abeta) peptide accumulation.
- This finding opens new avenues for therapeutic interventions in conditions associated with Abeta pathology.