Journal Article

In vivo regulation of the A disintegrin and metalloproteinase 10 (ADAM10) by the tetraspanin 15

Altmeppen, Hermann, Sedlacek, Radislav, Kasparek, Petr, Saftig, Paul, Tholey, Andreas, Glatzel, Markus, Seipold, Lisa, Bär, Julia, Koudelka, Tomas, Mikhaylova, Marina, Schweizer, Michaela

2018

Overview

A disintegrin and metalloproteinase 10 (ADAM10) plays a major role in the ectodomain shedding of important surface molecules with physiological and pathological relevance including the amyloid precursor protein (APP), the cellular prion protein, and different cadherins. Despite its therapeutic potential, there is still a considerable lack of knowledge how this protease is regulated. We have previously identified tetraspanin15 (Tspan15) as a member of the TspanC8 family to specifically associate with ADAM10. Cell-based overexpression experiments revealed that this binding affected the maturation process and surface expression of the protease. Our current study shows that Tspan15 is abundantly expressed in mouse brain, where it specifically interacts with endogenous ADAM10. Tspan15 knockout mice did not reveal an overt phenotype but showed a pronounced decrease of the active and mature form of ADAM10, an effect which augmented with aging. The decreased expression of active ADAM10 correlated with an age-dependent reduced shedding of neuronal (N)-cadherin and the cellular prion protein. APP α-secretase cleavage and the expression of Notch-dependent genes were not affected by the loss of Tspan15, which is consistent with the hypothesis that different TspanC8s cause ADAM10 to preferentially cleave particular substrates. Analyzing spine morphology revealed no obvious differences between Tspan15 knockout and wild-type mice. However, Tspan15 expression was elevated in brains of an Alzheimer’s disease mouse model and of patients, suggesting that upregulation of Tspan15 expression reflects a cellular response in a disease state. In conclusion, our data show that Tspan15 and most likely also other members of the TspanC8 family are central modulators of ADAM10-mediated ectodomain shedding in vivo.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: ADAM10 Protein - genetics / ADAM10 Protein - metabolism / Aging / Alzheimer disease / Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer's disease / amyloid / Amyloid precursor protein / animal models / Animals / Biochemistry / Biomedical and Life Sciences / Biomedicine / Brain / Brain - metabolism / Cadherins / Cell Biology / Cells, Cultured / Gene expression / Gene Expression Profiling - methods / Gene Expression Regulation / genes / Humans / knockout mutants / Life Sciences / metalloproteinases / mice / Mice, Inbred C57BL / Mice, Knockout / Modulators / Neurodegenerative diseases / Neuromodulation / neurons / Neurons - metabolism / Original / Original Article / patients / phenotype / Phenotypes / Prion protein / prions / Protease / Protein Binding / Proteinase / Proteins / Rats / Rodents / Secretase / Shedding / Spine / Substrates / Synapses - metabolism / Tetraspanins - genetics / Tetraspanins - metabolism / therapeutics