The Icelandic Mutation in the Murine APP Gene, mAPP, on Amyloid-β Plaque Burden in the 5×FAD Alzheimer Model.

Abstract

BACKGROUND: The protective Icelandic mutation in the amyloid precursor protein () gene, APP, 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 human APPmutation in various knock-in models of AD, but the effect of the mouse APPform in 5× familial AD (5×FAD) mice has never been investigated. METHODS: We crossed C57Bl6/J mice expressing a single point mutation edited into the murinegene via Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated (CRISPR-Cas) gene editing, termed mAPP, with 5×FAD 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 5×FAD × mAPPmice. We investigated amyloid beta-protein (Aβ) pathology in 5×FAD × mAPP, 5×FAD and their respective controls, mAPP, and C57Bl6/J wild type mice, at 6-months of age using immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay (ELISA). RESULTS: We found a moderate yet significant reduction in Aβ plaque size in male 5×FAD × mAPPcompared with 5×FAD mice. No differences were observed for soluble/insoluble Aβ40 and Aβ42 levels, but lower plaque count/area was found in 5×FAD × mAPPmice when Aβ42/Aβ40 ratios were low, suggesting a genotype-dependent sensitivity to Aβ aggregation and accumulation. CONCLUSIONS: The mAPPmutation has the potential to modify Aβ pathology in 5×FAD mice at the age of 6 months.