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- Title
The metalloprotease ADAMTS4 generates N-truncated Aβ4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer's disease.
- Authors
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; Weggen, Sascha
- 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.
- Subjects
METALLOPROTEINASES; OLIGODENDROGLIA; ALZHEIMER'S disease
- Publication
Acta Neuropathologica, 2019, Vol 137, Issue 2, p239
- ISSN
0001-6322
- Publication type
Article
- DOI
10.1007/s00401-018-1929-5