Dipeptidyl-Peptidase Activity of Meprin β Links N-truncation of Aβ with Glutaminyl Cyclase-Catalyzed pGlu-Aβ Formation.

The formation of amyloid-beta (A beta) peptides is causally involved in the development of Alzheimer's disease (AD). A significant proportion of deposited A beta is N-terminally truncated and modified at the N-terminus by a pGlu-residue (pGlu-A beta). These forms show enhanced neurotoxicity compared to full-length A beta. Although the truncation may occur by aminopeptidases after formation of A beta, recently discovered processing pathways of amyloid-beta protein precursor (A beta PP) by proteases such as meprin beta may also be involved. Here, we assessed a role of meprin beta in forming A beta(3-40/42), which is the precursor of pGlu-A beta(3-40/42 )generated by glutaminyl cyclase (QC) Similar to QC, meprin beta mRNA is significantly upregulated in postmortem brain from AD patients. A histochemical analysis supports the presence of meprin beta in neurons and astrocytes in the vicinity of pGlu-A beta containing deposits. Cleavage of A beta PP-derived peptides by meprin beta in vitro results in peptides A beta(1-)(x), A beta(2-x), and A beta(3-x). The formation of N-truncated A beta by meprin beta was also corroborated in cell culture. A subset of the generated peptides was converted into pGlu-A beta(3-40) by an addition of glutaminyl cyclase, supporting the preceding formation of A beta(3-40). Further analysis of the meprin beta cleavage revealed a yet unknown dipeptidyl-peptidase-like activity specific for the N-terminus of A beta(1-)(x). Thus, our data suggest that meprin beta contributes to the formation of N-truncated A beta by endopeptidase and exopeptidase activity to generate the substrate for QC-catalyzed pGlu-A beta formation.