The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease
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.
KeywordsNeurodegeneration Alzheimer’s disease Amyloidosis Aβ peptides N-truncation ADAMTS proteases Oligodendrocytes
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.
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.
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.).
Compliance with ethical standards
Conflict of interest
D.B. is the Chief Executive Officer of Asceneuron SA. All other authors declare that they have no conflict of interest.
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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