| First Author | Zhang X | Year | 2021 |
| Journal | J Exp Med | Volume | 218 |
| Issue | 6 | PubMed ID | 33822840 |
| Mgi Jnum | J:343865 | Mgi Id | MGI:6724829 |
| Doi | 10.1084/jem.20210313 | Citation | Zhang X, et al. (2021) An APP ectodomain mutation outside of the Abeta domain promotes Abeta production in vitro and deposition in vivo. J Exp Med 218(6) |
| abstractText | Familial Alzheimer's disease (FAD)-linked mutations in the APP gene occur either within the Abeta-coding region or immediately proximal and are located in exons 16 and 17, which encode Abeta peptides. We have identified an extremely rare, partially penetrant, single nucleotide variant (SNV), rs145081708, in APP that corresponds to a Ser198Pro substitution in exon 5. We now report that in stably transfected cells, expression of APP harboring the S198P mutation (APPS198P) leads to elevated production of Abeta peptides by an unconventional mechanism in which the folding and exit of APPS198P from the endoplasmic reticulum is accelerated. More importantly, coexpression of APP S198P and the FAD-linked PS1DeltaE9 variant in the brains of male and female transgenic mice leads to elevated steady-state Abeta peptide levels and acceleration of Abeta deposition compared with age- and gender-matched mice expressing APP and PS1DeltaE9. This is the first AD-linked mutation in APP present outside of exons 16 and 17 that enhances Abeta production and deposition. |
