The effect of the Icelandic mutation APP ^A673T in the line 66 model of tauopathy

The Icelandic mutation in the amyloid precursor protein (APP), APP ^A673T , has been identified in Icelandic and Scandinavian populations and is associated with a significantly lower risk of developing Alzheimer’s disease (AD). Although this mutation led to reduction in amyloid β-protein (Aβ) production, its effect on tau pathology is not well studied. We have crossed line 66 (L66) tau transgenic mice that overexpress the P301S aggregation-prone form of tau with C57Bl6/J mice expressing a single point mutation edited into the murine APP gene via CRISPR-Cas gene editing, termed APP ^A673T . We have performed ELISA, histopathological and behavioural analyses of heterozygous male/female L66 and L66xAPP ^A673T crosses at the age of 6 months to investigate the effect of the A673T mutation on tau brain pathology and behavioural deficits in these mice. Using immunohistochemistry, we found only a moderate, yet significant, reduction of mAb 7/51-reactive tau in prefrontal cortex for L66xAPP ^A673T compared to L66 mice. Quantification of tau in soluble/insoluble brain homogenate fractions by ELISA confirmed the lack of overt differences between genotypes, as did our extensive behavioural phenotyping using six different paradigms accessing motor function, olfaction, depression/apathy-like behaviour, as well as exploration and sociability. Therefore, the APP ^A673T mutation does not appear to modulate tau pathology or motor and neuropsychiatric behaviour in L66 tau transgenic mice.