The Icelandic mutation APP ^A673T on amyloid-β plaque burden in the 5xFAD Alzheimer model

The protective Icelandic mutation in the amyloid precursor protein (APP) gene, APP ^A673T , identified in Icelandic and other Nordic populations is associated with a significantly lower risk of developing Alzheimer’s disease (AD). Conflicting results have been reported for the APP ^A673T mutation in various knock-in models of AD, but its effect in 5x familial AD (5xFAD) mice has never been investigated. We have crossed C57Bl6/J mice expressing a single point mutation edited into the murine APP gene via CRISPR-Cas gene editing, termed APP ^A673T , with 5xFAD mice that overexpress human APP carrying the Swedish (K670N/M671L), Florida (I716V), and London (V717I) mutations as well as human presenilin-1 (PS1) with two mutations (M146L and L286V); the resulting mice were termed 5xFADxAPP ^A673T . We have investigated amyloid beta (Aβ) pathology in 5xFADxAPP ^A673T , 5xFAD and their respective controls, APP ^A673T and C57Bl6/J wild types, at 6-months of age using immunohistochemistry, immunoblotting, and ELISAs. We found a moderate yet significant reduction for Aβ plaque size in male 5xFADxAPP ^A673T compared to 5xFAD. No differences were observed for soluble/insoluble Aβ40 and Aβ42 levels per se, but lower plaque count/area was found in 5xFADxAPP ^A673T when Aβ42/Aβ40 ratios were low, suggesting a genotype-dependent sensitivity to Aβ aggregation and accumulation. Therefore, the APP ^A673T mutation has the potential to modify Aβ pathology in 5xFAD mice at the age of 6 months.