| First Author | Walter S | Year | 2019 |
| Journal | Acta Neuropathol | Volume | 137 |
| Issue | 2 | Pages | 239-257 |
| PubMed ID | 30426203 | Mgi Jnum | J:345764 |
| Mgi Id | MGI:6863631 | Doi | 10.1007/s00401-018-1929-5 |
| Citation | Walter S, et al. (2019) The metalloprotease ADAMTS4 generates N-truncated Abeta4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer's disease. Acta Neuropathol 137(2):239-257 |
| abstractText | Brain accumulation and aggregation of amyloid-beta (Abeta) peptides is a critical step in the pathogenesis of Alzheimer's disease (AD). Full-length Abeta peptides (mainly Abeta1-40 and Abeta1-42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble Abeta peptides are truncated at the N-terminus, with Abeta4-x peptides being particularly abundant. Abeta4-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 Abeta peptide sequence, which facilitates Abeta4-x peptide generation. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of Abeta4-40 but unchanged levels of Abeta1-x peptides. In the 5xFAD mouse model of amyloidosis, Abeta4-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, Abeta4-40 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 Abeta species, but Abeta4-40 peptides were absent in cultures derived from ADAMTS4(-/-) mice indicating that the enzyme was essential for Abeta4-x production in this cell type. These findings establish an enzymatic mechanism for the generation of Abeta4-x peptides. They further identify oligodendrocytes as a source of these highly amyloidogenic Abeta peptides. |
