| First Author | Stemmer N | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 4 | Pages | e61299 |
| PubMed ID | 23585889 | Mgi Jnum | J:206895 |
| Mgi Id | MGI:5553221 | Doi | 10.1371/journal.pone.0061299 |
| Citation | Stemmer N, et al. (2013) Generation of amyloid-beta is reduced by the interaction of calreticulin with amyloid precursor protein, presenilin and nicastrin. PLoS One 8(4):e61299 |
| abstractText | Dysregulation of the proteolytic processing of amyloid precursor protein by gamma-secretase and the ensuing generation of amyloid-beta is associated with the pathogenesis of Alzheimer's disease. Thus, the identification of amyloid precursor protein binding proteins involved in regulating processing of amyloid precursor protein by the gamma-secretase complex is essential for understanding the mechanisms underlying the molecular pathology of the disease. We identified calreticulin as novel amyloid precursor protein interaction partner that binds to the gamma-secretase cleavage site within amyloid precursor protein and showed that this Ca(2+)- and N-glycan-independent interaction is mediated by amino acids 330-344 in the C-terminal C-domain of calreticulin. Co-immunoprecipitation confirmed that calreticulin is not only associated with amyloid precursor protein but also with the gamma-secretase complex members presenilin and nicastrin. Calreticulin was detected at the cell surface by surface biotinylation of cells overexpressing amyloid precursor protein and was co-localized by immunostaining with amyloid precursor protein and presenilin at the cell surface of hippocampal neurons. The P-domain of calreticulin located between the N-terminal N-domain and the C-domain interacts with presenilin, the catalytic subunit of the gamma-secretase complex. The P- and C-domains also interact with nicastrin, another functionally important subunit of this complex. Transfection of amyloid precursor protein overexpressing cells with full-length calreticulin leads to a decrease in amyloid-beta42 levels in culture supernatants, while transfection with the P-domain increases amyloid-beta40 levels. Similarly, application of the recombinant P- or C-domains and of a synthetic calreticulin peptide comprising amino acid 330-344 to amyloid precursor protein overexpressing cells result in elevated amyloid-beta40 and amyloid-beta42 levels, respectively. These findings indicate that the interaction of calreticulin with amyloid precursor protein and the gamma-secretase complex regulates the proteolytic processing of amyloid precursor protein by the gamma-secretase complex, pointing to calreticulin as a potential target for therapy in Alzheimer's disease. |
