P391 - SEEDING AND SPREADING PROPERTIES OF TAU IN RAPIDLY PROGRESSIVE ALZHEIMER’S DISEASE (ID 2115)
Abstract
Aims
Clinical phenotypic heterogeneity of Alzheimer’s disease (AD) is well established. The rapidly progressive subtype of AD (rpAD), often misdiagnosed as Creutzfeldt-Jakob disease, has a specific phenotype (unusual symptoms, shorter disease duration and faster cognitive decline than classic AD (cAD)) that may be related to a different tau strain.
Methods
We investigated the properties of tau aggregates from patient brain preparations through different approaches: biochemistry (sucrose density gradient ultracentrifugation) (n=5 cAD , n=5 rpAD , n=2 CTRL cases), in vitro (Tau RD P301S FRET Biosensor cells) (n=2 cAD , n=2 rpAD , n=2 CTRL) and in vivo (hippocampal inoculations in the P301S mice) (n=8 cAD , n=8 rpAD , n=8 CTRL) studies.
Results
Pathological tau from cAD patients showed a higher propensity to seed aggregation and spread than that from rpAD cases: 1)Tau pathology was seen at a greater distance in cAD- than in rpAD-injected P301S mice, 2) Tau aggregates were more numerous in Tau RD P301S FRET Biosensor cells exposed to cAD vs rpAD homogenates, 3) Tau in cAD patients formed denser assemblies, as seen with sucrose density gradient ultracentrifugation.
Conclusions
Through different approaches we showed that pathological tau species in cAD and rpAD have distinct seeding and spreading properties suggesting the presence of different tau strains. The paradoxical results we obtained with rpAD brain extracts (low seeding and spreading potential) suggest that the specificity of the rpAD variant might rely on a predominance of specific small (eg oligomeric) tau assemblies that remain to be identified.
