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

Acta Neuropathol. 2019 Feb;137(2):239-257. doi: 10.1007/s00401-018-1929-5. Epub 2018 Nov 13.


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.

Keywords: ADAMTS proteases; Alzheimer’s disease; Amyloidosis; Aβ peptides; N-truncation; Neurodegeneration; Oligodendrocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS4 Protein / metabolism*
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • HEK293 Cells
  • Humans
  • Mice
  • Oligodendroglia / metabolism*
  • Oligodendroglia / pathology
  • Peptide Fragments / metabolism
  • Plaque, Amyloid / pathology


  • Amyloid beta-Peptides
  • Peptide Fragments
  • Amyloid Precursor Protein Secretases
  • ADAMTS4 Protein
  • ADAMTS4 protein, human
  • Adamts4 protein, mouse