Affiliations: [a]
Department of Molecular Drug Design and Target Validation Fraunhofer Institute for Cell Therapy and Immunology, Halle (Saale), Germany
| [b]
Paul Flechsig Institute for Brain Research, Leipzig, Germany
Correspondence:
[*]
Correspondence to: Stephan Schilling and Hans-Ulrich Demuth, Fraunhofer Institute for Cell Therapy and Immunology, Department of Molecular Drug Design and Target Validation, Weinbergweg 22, 06120 Halle (Saale), Germany. Tel.: +49 34513142800; Fax: +49 34513142801; E-mails: stephan.schilling@izi.fraunhofer.de and hans-ulrich. demuth@izi.fraunhofer.de.
Note: [1] These authors contributed equally to this work.
Abstract: The formation of amyloid-β (Aβ) peptides is causally involved in the development of Alzheimer’s disease (AD). A significant proportion of deposited Aβ is N-terminally truncated and modified at the N-terminus by a pGlu-residue (pGlu-Aβ). These forms show enhanced neurotoxicity compared to full-length Aβ. Although the truncation may occur by aminopeptidases after formation of Aβ, recently discovered processing pathways of amyloid-β protein precursor (AβPP) by proteases such as meprin β may also be involved. Here, we assessed a role of meprin β in forming Aβ3-40/42, which is the precursor of pGlu-Aβ3-40/42 generated by glutaminyl cyclase (QC). Similar to QC, meprin β mRNA is significantly upregulated in postmortem brain from AD patients. A histochemical analysis supports the presence of meprin β in neurons and astrocytes in the vicinity of pGlu-Aβ containing deposits. Cleavage of AβPP-derived peptides by meprin β in vitro results in peptides Aβ1-x, Aβ2-x, and Aβ3-x. The formation of N-truncated Aβ by meprin β was also corroborated in cell culture. A subset of the generated peptides was converted into pGlu-Aβ3-40 by an addition of glutaminyl cyclase, supporting the preceding formation of Aβ3-40. Further analysis of the meprin β cleavage revealed a yet unknown dipeptidyl-peptidase–like activity specific for the N-terminus of Aβ1-x. Thus, our data suggest that meprin β contributes to the formation of N-truncated Aβ by endopeptidase and exopeptidase activity to generate the substrate for QC-catalyzed pGlu-Aβ formation.
