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), APPA673T, 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 APPA673T form led to a reduction in amyloid β-protein (Aβ) production and tau pathology, but the effect of mouse APPA673T 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 APP gene via CRISPR-Cas gene editing, known as mAPPA673T. We have performed ELISA, histopathological, and behavioural analyses of heterozygous male/female L66 and L66 xmAPPA673T 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 mAPPA673T 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 mAPPA673T mutation has a moderate impact on tau pathology but does not appear to impact motor and neuropsychiatric behaviour in L66 tau transgenic mice.