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

ABSTRACT

Familial Alzheimer's disease (FAD)-linked mutations in the APP gene occur either within the Aß-coding region or immediately proximal and are located in exons 16 and 17, which encode Aß 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 Aß 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 Aß peptide levels and acceleration of Aß deposition compared with age- and gender-matched mice expressing APP and PS1ΔE9. This is the first AD-linked mutation in APP present outside of exons 16 and 17 that enhances Aß production and deposition.