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

Walter, Susanne; Jumpertz, Thorsten; Hüttenrauch, Melanie; Ogorek, Isabella; Gerber, Hermeto; Storck, Steffen E.; Zampar, Silvia; Dimitrov, Mitko; Lehmann, Sandra; Lepka, Klaudia; Berndt, Carsten; Wiltfang, Jens; Becker-Pauly, Christoph; Beher, Dirk; Pietrzik, Claus U.; Fraering, Patrick C.; Wirths, Oliver

doi:10.1007/s00401-018-1929-5

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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

Walter, Susanne Department of Neuropathology, Heinrich-Heine University, Düsseldorf, Germany
Jumpertz, Thorsten Department of Neuropathology, Heinrich-Heine University, Düsseldorf, Germany
Hüttenrauch, Melanie Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Goettingen, Germany
Ogorek, Isabella Department of Neuropathology, Heinrich-Heine University, Düsseldorf, Germany
Gerber, Hermeto Foundation Eclosion, Geneva, Switzerland - Department of Biology, University of Fribourg, Fribourg, Switzerland
Storck, Steffen E. Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
Zampar, Silvia Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Goettingen, Germany
Dimitrov, Mitko Brain Mind Institute, Swiss Federal Institute of Technology, Lausanne, Switzerland
Lehmann, Sandra Department of Neuropathology, Heinrich-Heine University, Düsseldorf, Germany
Lepka, Klaudia Department of Neurology, Heinrich-Heine University, Düsseldorf, Germany
Berndt, Carsten Department of Neurology, Heinrich-Heine University, Düsseldorf, Germany
Wiltfang, Jens Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Goettingen, Germany
Becker-Pauly, Christoph Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany
Beher, Dirk Asceneuron SA, EPFL Innovation Park, Lausanne, Switzerland
Pietrzik, Claus U. Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
Fraering, Patrick C. Foundation Eclosion, Geneva, Switzerland
Wirths, Oliver Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Goettingen, Germany

01.02.2019

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Acta Neuropathologica. - 2019, vol. 137, no. 2, p. 239–257

English 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.

Faculty

Faculté des sciences et de médecine

Department

Département de Biologie

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