Effect of the Icelandic Mutation APPA673T in the Murine APP Gene on Phenotype of Line 66 Tau Mice

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). The introduction of the human APP^A673T form led to a reduction in amyloid β-protein (Aβ) production and tau pathology, but the effect of mouse APP^A673T on tau and Aβ 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 <i>APP</i> gene via CRISPR-Cas gene editing, known as mAPP^A673T. We have performed ELISA, histopathological, and behavioural analyses of heterozygous male/female L66 and L66 xmAPP^A673T crosses at the age of 6 months to investigate the effect of the murine A673T mutation on tau brain pathology and behavioural deficits in these mice. Using immunohistochemistry, we found only a moderate, yet significant, reduction in mAb 7/51-reactive tau for female L66 x mAPP^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 assessing motor function, olfaction, depression/apathy-like behaviour, as well as exploration and sociability. Therefore, the mAPP^A673T mutation has a moderate impact on tau pathology but does not appear to impact motor and neuropsychiatric behaviour in L66 tau transgenic mice.