| First Author | Szaruga M | Year | 2017 |
| Journal | Cell | Volume | 170 |
| Issue | 3 | Pages | 443-456.e14 |
| PubMed ID | 28753424 | Mgi Jnum | J:252789 |
| Mgi Id | MGI:5926548 | Doi | 10.1016/j.cell.2017.07.004 |
| Citation | Szaruga M, et al. (2017) Alzheimer's-Causing Mutations Shift Abeta Length by Destabilizing gamma-Secretase-Abetan Interactions. Cell 170(3):443-456.e14 |
| abstractText | Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor protein (APP) lead to production of longer amyloidogenic Abeta peptides. The shift in Abeta length is fundamental to the disease; however, the underlying mechanism remains elusive. Here, we show that substrate shortening progressively destabilizes the consecutive enzyme-substrate (E-S) complexes that characterize the sequential gamma-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutations further destabilize labile E-S complexes and thereby promote generation of longer Abeta peptides. Similarly, destabilization of wild-type E-S complexes by temperature, compounds, or detergent promotes release of amyloidogenic Abeta. In contrast, E-Abetan stabilizers increase gamma-secretase processivity. Our work presents a unifying model for how PSEN or APP mutations enhance amyloidogenic Abeta production, suggests that environmental factors may increase AD risk, and provides the theoretical basis for the development of gamma-secretase/substrate stabilizing compounds for the prevention of AD. |
