AMYLOID β-PROTEIN OLIGOMERS PROMOTE THE UPTAKE OF TAU FIBRIL SEEDS POTENTIATING INTRACELLULAR TAU AGGREGATION

Abstract

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-β (Aβ) and tau proteins in AD but the molecular details of how these interactions drive AD pathology remain elusive. Here, we asked whether Aβ potentiates intracellular tau aggregation. We also explored to what extent the assembly state of Aβ might contribute to this process. Using tau-biosensor cells, we show that treatment with sub-toxic concentrations of Aβ oligomers, but not monomers or fibrils, “primes” the cells and makes them susceptible to tau seeding. The treatment with Aβ 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 Aβ-oligomer priming. Priming by Aβ oligomers appears to be specific to tau, as α-synuclein seeding is unaffected by this treatment. Aβ oligomer-enhanced tau seeding also occurs in primary mouse neurons and human neuroblastoma cells. Using fluorescently labeled tau seeds, we found that treatment with Aβ oligomers significantly enhanced the cellular uptake of the seeds, whereas a known tau-uptake inhibitor blocked Aβ promoted tau seeding. The ability of Aβ to promote tau seeding suggests a deleterious mechanism unique to AD and may explain why therapies focused on just one of the offending proteins have not been successful to date.