RELEVANCE OF TAU SEEDING FOR THE CLINICAL HETEROGENEITY OF ALZHEIMER’S DISEASE: IMPLICATION FOR THERAPEUTIC PERSPECTIVES

Alzheimer's disease (AD) is a progressive disorder, where symptoms gradually appear over the course of several years. This progression is however very heterogenous from patient-to-patient from a couple of years to more than 20 years. Cognitive decline in AD was also shown to correlate with aggregation and spread of tau proteins. This spread of aggregated tau proteins through neural networks is a novel concept involving trans-synaptic transfer of pathological tau species and seeding of tau aggregation. Small tau aggregates –so-called seeds– can induce fibrillization of intracellular non-aggregated tau via direct contact. Tau “seeds” can be isolated from either tau-transgenic mice or tauopathy-positive human brains. We wondered if tau seeding could explain, at least in part, the heterogeneity of human AD progression and if this has an impact on the potential of tau seeding-targeted immunotherapy. We particularly aimed to 1-understand how tau seeding can be linked to clinical, anatomical and pathological characteristics and 2-try to reduce tau seeding with the use of diverse anti-tau antibodies. We selected a cohort of over 30 human AD patients based on clinical and neuropathological records. We quantified tau seeding from these brains using a FRET-based cellular assay and systematically performed different histological, biochemical and cellular characterizations for each patient. Lastly, we tried to reduce seeding activity using diverse anti-tau antibodies. We found a high degree of heterogeneity of tau seeding among cases. Interestingly, this variability closely correlates with the speed of clinical progression and the age of onset of AD. As expected, histological tangle burden also correlates closely. In addition, with biochemical characterizations, these results suggest that only a small fraction of the total amount of tau present in the brain is capable to induce seeding. This ‘bioactive’ tau fraction is however very relevant to the human pathology and clinical symptoms. Antibodies targeting total or post-translationally modified tau significantly reduced tau seeding but each brain sample displayed unique sensitivity to reduction arguing for the existence of various “bioactive” tau “strains”. these results provide a novel characterization of the relevance of tau seeding in AD and add insights into the therapeutic potential of tau immunotherapy.