THE ROLE OF TAU STRAINS IN PHENOTYPIC VARIABILITY IN ALZHEIMER’S DISEASE

Clinical phenotypic heterogeneity of Alzheimer’s disease (AD) is well established. Rapidly progressive subtype of AD (rpAD) has a specific phenotype (unusual symptoms, shorter disease duration and faster cognitive decline than classic AD (cAD)) suggesting a different potential tau strain.
We have investigated tau protein characteristics through different approaches: biochemistry (sucrose gradient sedimentation) (n=5 cAD , n=5 rpAD , n=2 CTRL cases), « in vitro » (HEK biosensor cell system) (n=2 cAD , n=2 rpAD , n=2 CTRL) and « in vivo » (hippocampal injections in tau P301S Tg mice) (n=8 cAD , n=8 rpAD , n=8 CTRL) studies.
We have observed a higher seeding activity of Tau-cAD compared with Tau-rpAD as seen in the “in vitro” and “in vivo” experiments. cAD brain homogenate induced higher amount of tau pathology than rpAD extracts when applied intracerebrally in tau-P301S mice or on tau P301S biosensor HEK cells. Tau in rpAD subjects is formed by less dense particles, probably corresponding to the presence of higher amount of oligomeric forms, as seen with sucrose gradient sedimentation.
These observations could be consistent with the existence of different tau conformers leading to distinct diseases.