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bioRxiv · 10.1101/2025.11.05.686739

The Icelandic mutation APPA673T on amyloid-β plaque burden in the 5xFAD Alzheimer model

Anschuetz, A.·Listyono, R.·Vorley, T.·Platt, B.·Harrington, C. R.·Riedel, G.·Schwab, K.
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Abstract

The protective Icelandic mutation in the amyloid precursor protein (APP) gene, APPA673T, identified in Icelandic and other Nordic populations is associated with a significantly lower risk of developing Alzheimers disease (AD). Conflicting results have been reported for the APPA673T 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 APPA673T, 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 5xFADxAPPA673T. We have investigated amyloid beta (A{beta}) pathology in 5xFADxAPPA673T, 5xFAD and their respective controls, APPA673T and C57Bl6/J wild types, at 6-months of age using immunohistochemistry, immunoblotting, and ELISAs. We found a moderate yet significant reduction for A{beta} plaque size in male 5xFADxAPPA673T compared to 5xFAD. No differences were observed for soluble/insoluble A{beta}40 and A{beta}42 levels per se, but lower plaque count/area was found in 5xFADxAPPA673T when A{beta}42/A{beta}40 ratios were low, suggesting a genotype-dependent sensitivity to A{beta} aggregation and accumulation. Therefore, the APPA673T mutation has the potential to modify A{beta} pathology in 5xFAD mice at the age of 6 months.

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Anschuetz, A., Listyono, R., Vorley, T., Platt, B., Harrington, C. R., Riedel, G., Schwab, K.. 2025-11-06. The Icelandic mutation APPA673T on amyloid-β plaque burden in the 5xFAD Alzheimer model. https://doi.org/10.1101/2025.11.05.686739

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