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The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease

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Abstract

Brain accumulation and aggregation of amyloid-β (Aβ) peptides is a critical step in the pathogenesis of Alzheimer’s disease (AD). Full-length Aβ peptides (mainly Aβ1–40 and Aβ1–42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble Aβ peptides are truncated at the N-terminus, with Aβ4–x peptides being particularly abundant. Aβ4–x peptides are highly aggregation prone, but their origin and any proteases involved in their generation are unknown. We have identified a recognition site for the secreted metalloprotease ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) in the Aβ peptide sequence, which facilitates Aβ4–x peptide generation. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of Aβ4–40 but unchanged levels of Aβ1–x peptides. In the 5xFAD mouse model of amyloidosis, Aβ4–x peptides were present not only in amyloid plaque cores and vessel walls, but also in white matter structures co-localized with axonal APP. In the ADAMTS4−/− knockout background, Aβ4–40 levels were reduced confirming a pivotal role of ADAMTS4 in vivo. Surprisingly, in the adult murine brain, ADAMTS4 was exclusively expressed in oligodendrocytes. Cultured oligodendrocytes secreted a variety of Aβ species, but Aβ4–40 peptides were absent in cultures derived from ADAMTS4−/− mice indicating that the enzyme was essential for Aβ4–x production in this cell type. These findings establish an enzymatic mechanism for the generation of Aβ4–x peptides. They further identify oligodendrocytes as a source of these highly amyloidogenic Aβ peptides.

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Acknowledgements

We thank Karlheinz Baumann and Manfred Brockhaus (F. Hoffmann-La Roche Ltd., Basel, Switzerland) for carboxyl terminus-specific Aβ antibodies, and Guido Reifenberger (Heinrich-Heine-University Duesseldorf, Germany) for encouragement and support.

Funding

This work was supported by grants from the Stiftung VERUM (to S.W.) and the Forschungskommission of the Medical Faculty of the Heinrich-Heine-University Duesseldorf (grant 9772513 to T.J. and S.W.), the Alzheimer Forschung Initiative (grant 16013 to O.W.), and the foundations Strauss, Eclosion and SFNTF (to H.G. and P.C.F.).

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  1. Department of Neuropathology, Heinrich-Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany

    Susanne Walter, Thorsten Jumpertz, Isabella Ogorek, Sandra Lehmann & Sascha Weggen

  2. Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, von-Siebold Strasse 5, 37075, Goettingen, Germany

    Melanie Hüttenrauch, Silvia Zampar, Jens Wiltfang & Oliver Wirths

  3. Foundation Eclosion, 1228 Plan-les-Ouates and Campus Biotech Innovation Park, 1202, Geneva, Switzerland

    Hermeto Gerber & Patrick C. Fraering

  4. Department of Biology, University of Fribourg, 1700, Fribourg, Switzerland

    Hermeto Gerber

  5. Brain Mind Institute, Swiss Federal Institute of Technology, 1015, Lausanne, Switzerland

    Mitko Dimitrov

  6. Department of Neurology, Heinrich-Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany

    Klaudia Lepka & Carsten Berndt

  7. Institute of Biochemistry, Christian-Albrechts-University, Otto-Hahn-Platz 9, 24118, Kiel, Germany

    Christoph Becker-Pauly

  8. Asceneuron SA, EPFL Innovation Park, 1015, Lausanne, Switzerland

    Dirk Beher

  9. Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, 55128, Mainz, Germany

    Steffen E. Storck & Claus U. Pietrzik

Authors
  1. Susanne Walter
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  2. Thorsten Jumpertz
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  3. Melanie Hüttenrauch
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  4. Isabella Ogorek
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  5. Hermeto Gerber
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  6. Steffen E. Storck
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  7. Silvia Zampar
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  8. Mitko Dimitrov
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  9. Sandra Lehmann
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  10. Klaudia Lepka
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  11. Carsten Berndt
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  12. Jens Wiltfang
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  13. Christoph Becker-Pauly
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  14. Dirk Beher
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  15. Claus U. Pietrzik
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  16. Patrick C. Fraering
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  17. Oliver Wirths
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  18. Sascha Weggen
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Contributions

SW, TJ, DB, OW and SW designed the study. SW, TJ, MH, HG, MD, IO, SL, KL, SZ, SES, and OW designed and performed experiments. SW, TJ, MH, HG., MD, IO, SL, CB, JW, CB-P, CUP, PCF, OW and SW analyzed data, discussed results and provided scientific input throughout the study. SW, OW and SW wrote the paper with input and approval from all authors.

Corresponding authors

Correspondence to Oliver Wirths or Sascha Weggen.

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Conflict of interest

D.B. is the Chief Executive Officer of Asceneuron SA. All other authors declare that they have no conflict of interest.

Ethical approval

All animal experiments were carried out in accordance with German guidelines for animal care and have been approved by the local responsible committee.

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Walter, S., Jumpertz, T., Hüttenrauch, M. et al. The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease. Acta Neuropathol 137, 239–257 (2019). https://doi.org/10.1007/s00401-018-1929-5

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  • DOI: https://doi.org/10.1007/s00401-018-1929-5

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