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

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Abstract

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.

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Abbreviations

AD:

Alzheimer’s disease

ADAM:

A Disintegrin And Metalloproteinase

APP:

Amyloid precursor protein

CA1:

CA1 layer of the hippocampus

CC:

Corpus callosum

CNS:

Central nervous system

cKO:

Conditional knockout

CTF:

C-terminal fragment

Cx:

Cortex

fl:

Full-length

GFAP:

Glial fibrillary acidic protein

GPI:

Glycosylphosphatidylinositol

IB:

Immunoblot

Iba1:

Ionized calcium-binding adaptor molecule 1

IP:

Immunoprecipitation

ko:

Knockout

LEL:

Large extracellular loop

LIMP-2:

Lysosomal integral membrane protein-2

NeuN:

Neuronal neuclei

PrPC :

Cellular prion protein

PrPSc :

Scrapie PrP

shPrPC :

Shed PrPC

PNGase F:

Peptide N-glycosidase F

PSD:

Postsynaptic density

SEL:

Small extracellular loop

Tspan:

Tetraspanin

TALEN:

Transcription activator-like effector nuclease

TEM:

Tetraspanin-enriched microdomain

wt:

Wild-type

5xFAD:

5 Familial AD mutations

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) Sonderforschungsbereich 877 [projects A3 (P.S.), Z2 (T.K., A.T.) and A12 (P.S., H.A., and M.G.)], the Creutzfeldt-Jakob Disease Foundation, Inc., and the Werner-Otto-Stiftung (to H.A.). R.S. was supported by CZ.1.05/2.1.00/19.0395 (MEYS) and Academy of Sciences of the Czech Republic (RVO 68378050). M. Mikhaylova is supported by grants from the Deutsche Forschungsgemeinschaft [DFG Emmy-Noether-Programm (Ml 1923/1-1) and FOR2419 (MI 1923/2-1)]. We gratefully thank Dr. Sebastian Wetzel and Dr. Dirk Schmidt-Arras for cloning the Tspan15-YPET construct. We also thank Kristin Hartmann (Mouse Pathology Core Unit, UKE, Hamburg) and Emanuela Szpotowicz and Chundamani Raithore (Prague) for valuable technical support.

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Authors and Affiliations

  1. Institute of Biochemistry, Christian Albrechts University Kiel, Olshausenstrasse 40, 24118, Kiel, Germany

    Lisa Seipold & Paul Saftig

  2. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany

    Hermann Altmeppen & Markus Glatzel

  3. Systematic Proteome Research and Bioanalytics, Institute for Experimental Medicine, Christian Albrechts University Kiel, Niemannsweg 11, Kiel, 24105, Germany

    Tomas Koudelka & Andreas Tholey

  4. Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics of the CAS, v. v. i, Vestec, Czech Republic

    Petr Kasparek & Radislav Sedlacek

  5. Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251, Hamburg, Germany

    Michaela Schweizer

  6. Center for Molecular Neurobiology Hamburg (ZMNH), Emmy-Noether Group “Neuronal Protein Transport”, University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251, Hamburg, Germany

    Julia Bär & Marina Mikhaylova

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  1. Lisa Seipold
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  2. Hermann Altmeppen
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  3. Tomas Koudelka
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  4. Andreas Tholey
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  5. Petr Kasparek
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  6. Radislav Sedlacek
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  9. Marina Mikhaylova
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  11. Paul Saftig
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Correspondence to Paul Saftig.

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Ethical standards

All animal studies were performed according to the guidelines of the Federation of European Laboratory Animal Science Associations (FELASA) and were approved by the animal welfare committee of the Ministry of Energy, Agriculture, the Environment, Nature and Digitalization, Schleswig-Holstein, Germany (protocols V242.7224.121-3, V242-80867/2016). The use of specimens and basic clinical information were in agreement with the regulations and ethical standards at the contributing hospitals and written consent by patients or relatives was obtained where necessary.

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Seipold, L., Altmeppen, H., Koudelka, T. et al. In vivo regulation of the A disintegrin and metalloproteinase 10 (ADAM10) by the tetraspanin 15. Cell. Mol. Life Sci. 75, 3251–3267 (2018). https://doi.org/10.1007/s00018-018-2791-2

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