| First Author | Sun L | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 4 | Pages | E476-E485 |
| PubMed ID | 27930341 | Mgi Jnum | J:240036 |
| Mgi Id | MGI:5882252 | Doi | 10.1073/pnas.1618657114 |
| Citation | Sun L, et al. (2017) Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Abeta42 and Abeta40 peptides by gamma-secretase. Proc Natl Acad Sci U S A 114(4):E476-E485 |
| abstractText | A hallmark of Alzheimer's disease (AD) is the aggregation of beta-amyloid peptides (Abeta) into amyloid plaques in patient brain. Cleavage of amyloid precursor protein (APP) by the intramembrane protease gamma-secretase produces Abeta of varying lengths, of which longer peptides such as Abeta42 are thought to be more harmful. Increased ratios of longer Abetas over shorter ones, exemplified by the ratio of Abeta42 over Abeta40, may lead to formation of amyloid plaques and consequent development of AD. In this study, we analyzed 138 reported mutations in human presenilin-1 (PS1) by individually reconstituting the mutant PS1 proteins into anterior-pharynx-defective protein 1 (APH-1)aL-containing gamma-secretases and examining their abilities to produce Abeta42 and Abeta40 in vitro. About 90% of these mutations lead to reduced production of Abeta42 and Abeta40. Notably, 10% of these mutations result in decreased Abeta42/Abeta40 ratios. There is no statistically significant correlation between the Abeta42/Abeta40 ratio produced by a gamma-secretase variant containing a specific PS1 mutation and the mean age at onset of patients from whom the mutation was isolated. |
