An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo.

ABSTRACT: Familial Alzheimer's disease (FAD)-linked mutations in the APP gene occur either within the Aβ-coding region or immediately proximal and are located in exons 16 and 17, which encode Aβ 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 Aβ 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 PS1ΔE9 variant in the brains of male and female transgenic mice leads to elevated steady-state Aβ peptid

SUBMITTER: Zhang X 

PROVIDER: S-EPMC8034382 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature