Amyloid β-protein oligomers promote the uptake of tau fibril seeds potentiating intracellular tau aggregation

Background Repeated failure of drug candidates targeting Alzheimer's disease (AD) in clinical trials likely stems from a lack of understanding of the molecular mechanisms underlying AD pathogenesis. Recent research has highlighted synergistic interactions between aggregated amyloid-beta (A beta) and tau proteins in AD, but the molecular details of how these interactions drive AD pathology remain elusive and speculative. Methods Here, we test the hypothesis that A beta potentiates intracellular tau aggregation, and show that oligomeric A beta specifically exacerbates proteopathic seeding by tau. Using tau-biosensor cells, we show that treatment with sub-toxic concentrations of A beta oligomers, but not monomers or fibrils, "primes" cells, making them more susceptible to tau seeding. The treatment with A beta oligomers enhances intracellular tau aggregation in a dose-dependent manner when the cells are seeded with either recombinant or brain-derived tau fibrils, whereas little or no aggregation is observed in the absence of A beta-oligomer priming. Results Priming by A beta oligomers appears to be specific to tau, as alpha-synuclein seeding is unaffected by this treatment. A beta oligomer-enhanced tau seeding also occurs in primary mouse neurons and human neuroblastoma cells. Using fluorescently labeled tau seeds, we find that treatment with A beta oligomers significantly enhances the cellular uptake of tau seeds, whereas a known tau-uptake inhibitor blocks the effect of A beta on tau uptake. Conclusion The ability of A beta to promote tau seeding suggests a specific and plausible mechanism by which extracellular A beta initiates a deleterious cascade that is unique to AD. These data suggest that the A beta-mediated potentiation of tau uptake into cells should also be taken into account when designing A beta-targeted therapeutics.