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Generation of aggregation prone N-terminally truncated amyloid β peptides by meprin β depends on the sequence specificity at the cleavage site.

Schönherr C, Bien J, Isbert S, Wichert R, Prox J, Altmeppen H, Kumar S, Walter J, Lichtenthaler SF, Weggen S, Glatzel M, Becker-Pauly C, Pietrzik CU - Mol Neurodegener (2016)

Bottom Line: We further analyzed the cellular interaction of APP and meprin β and found that cleavage of APP by meprin β occurs prior to endocytosis.The N-terminally truncated Aβ2-40 variant shows increased aggregation propensity compared to Aβ1-40 and acts even as a seed for Aβ1-40 aggregation.Concluding, we propose that meprin β may be involved in the generation of N-terminally truncated Aβ2-x peptides of APP, but acts independently from BACE-1.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Duesbergweg 6, 55128, Mainz, Germany.

ABSTRACT

Background: The metalloprotease meprin β cleaves the Alzheimer's Disease (AD) relevant amyloid precursor protein (APP) as a β-secretase reminiscent of BACE-1, however, predominantly generating N-terminally truncated Aβ2-x variants.

Results: Herein, we observed increased endogenous sAPPα levels in the brains of meprin β knock-out (ko) mice compared to wild-type controls. We further analyzed the cellular interaction of APP and meprin β and found that cleavage of APP by meprin β occurs prior to endocytosis. The N-terminally truncated Aβ2-40 variant shows increased aggregation propensity compared to Aβ1-40 and acts even as a seed for Aβ1-40 aggregation. Additionally, we observed that different APP mutants affect the catalytic properties of meprin β and that, interestingly, meprin β is unable to generate N-terminally truncated Aβ peptides from Swedish mutant APP (APPswe).

Conclusion: Concluding, we propose that meprin β may be involved in the generation of N-terminally truncated Aβ2-x peptides of APP, but acts independently from BACE-1.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the proteolytic cleavage of APP by meprin β. We found molecular interaction of APP and the metalloprotease meprin β in the secretory pathway and at the cell surface. On the right site, specific antibodies for APP/APP fragments and their epitopes are marked. Note that the neo-epitope 192wt antibody only recognizes “full-length” sAPPβ having methionine at the C-terminus, while the shorter sAPPβ starting with lysine produced via meprin β cleavage cannot be detected
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Fig1: Schematic representation of the proteolytic cleavage of APP by meprin β. We found molecular interaction of APP and the metalloprotease meprin β in the secretory pathway and at the cell surface. On the right site, specific antibodies for APP/APP fragments and their epitopes are marked. Note that the neo-epitope 192wt antibody only recognizes “full-length” sAPPβ having methionine at the C-terminus, while the shorter sAPPβ starting with lysine produced via meprin β cleavage cannot be detected

Mentions: The relevance of the protease for APP processing is further highlighted by its activity on endogenous APP in the mouse brain. Additionally we demonstrate that meprin β cleavage of APP occurs prior to the endocytic compartments, as diminished APP endocytosis has no influence on meprin β mediated Aβ generation (summarized in Fig. 1). Moreover, we are able to demonstrate that meprin β generates N-terminally truncated Aβ2-40/42 peptides that display increased aggregation compared to non-truncated Aβ peptides. This catalytic activity of meprin β is differentially affected by mutated forms of APP and in contrast to wt APP, meprin β is not able to cleave APPswe at position 672 and does not generate N-terminally truncated forms of Aβ from this APP mutant.Fig. 1


Generation of aggregation prone N-terminally truncated amyloid β peptides by meprin β depends on the sequence specificity at the cleavage site.

Schönherr C, Bien J, Isbert S, Wichert R, Prox J, Altmeppen H, Kumar S, Walter J, Lichtenthaler SF, Weggen S, Glatzel M, Becker-Pauly C, Pietrzik CU - Mol Neurodegener (2016)

Schematic representation of the proteolytic cleavage of APP by meprin β. We found molecular interaction of APP and the metalloprotease meprin β in the secretory pathway and at the cell surface. On the right site, specific antibodies for APP/APP fragments and their epitopes are marked. Note that the neo-epitope 192wt antibody only recognizes “full-length” sAPPβ having methionine at the C-terminus, while the shorter sAPPβ starting with lysine produced via meprin β cleavage cannot be detected
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4759862&req=5

Fig1: Schematic representation of the proteolytic cleavage of APP by meprin β. We found molecular interaction of APP and the metalloprotease meprin β in the secretory pathway and at the cell surface. On the right site, specific antibodies for APP/APP fragments and their epitopes are marked. Note that the neo-epitope 192wt antibody only recognizes “full-length” sAPPβ having methionine at the C-terminus, while the shorter sAPPβ starting with lysine produced via meprin β cleavage cannot be detected
Mentions: The relevance of the protease for APP processing is further highlighted by its activity on endogenous APP in the mouse brain. Additionally we demonstrate that meprin β cleavage of APP occurs prior to the endocytic compartments, as diminished APP endocytosis has no influence on meprin β mediated Aβ generation (summarized in Fig. 1). Moreover, we are able to demonstrate that meprin β generates N-terminally truncated Aβ2-40/42 peptides that display increased aggregation compared to non-truncated Aβ peptides. This catalytic activity of meprin β is differentially affected by mutated forms of APP and in contrast to wt APP, meprin β is not able to cleave APPswe at position 672 and does not generate N-terminally truncated forms of Aβ from this APP mutant.Fig. 1

Bottom Line: We further analyzed the cellular interaction of APP and meprin β and found that cleavage of APP by meprin β occurs prior to endocytosis.The N-terminally truncated Aβ2-40 variant shows increased aggregation propensity compared to Aβ1-40 and acts even as a seed for Aβ1-40 aggregation.Concluding, we propose that meprin β may be involved in the generation of N-terminally truncated Aβ2-x peptides of APP, but acts independently from BACE-1.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Duesbergweg 6, 55128, Mainz, Germany.

ABSTRACT

Background: The metalloprotease meprin β cleaves the Alzheimer's Disease (AD) relevant amyloid precursor protein (APP) as a β-secretase reminiscent of BACE-1, however, predominantly generating N-terminally truncated Aβ2-x variants.

Results: Herein, we observed increased endogenous sAPPα levels in the brains of meprin β knock-out (ko) mice compared to wild-type controls. We further analyzed the cellular interaction of APP and meprin β and found that cleavage of APP by meprin β occurs prior to endocytosis. The N-terminally truncated Aβ2-40 variant shows increased aggregation propensity compared to Aβ1-40 and acts even as a seed for Aβ1-40 aggregation. Additionally, we observed that different APP mutants affect the catalytic properties of meprin β and that, interestingly, meprin β is unable to generate N-terminally truncated Aβ peptides from Swedish mutant APP (APPswe).

Conclusion: Concluding, we propose that meprin β may be involved in the generation of N-terminally truncated Aβ2-x peptides of APP, but acts independently from BACE-1.

No MeSH data available.


Related in: MedlinePlus