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

Abstract

BackgroundRepeated 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 and speculative.MethodsHere, we test the hypothesis that Aβ potentiates intracellular tau aggregation, and show that oligomeric Aβ specifically exacerbates proteopathic seeding by tau. Using tau-biosensor cells, we show that treatment with sub-toxic concentrations of Aβ oligomers, but not monomers or fibrils, “primes” cells, making them more 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.ResultsPriming 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 find that treatment with Aβ oligomers significantly enhances the cellular uptake of tau seeds, whereas a known tau-uptake inhibitor blocks the effect of Aβ on tau uptake.ConclusionThe ability of Aβ to promote tau seeding suggests a specific and plausible mechanism by which extracellular Aβ initiates a deleterious cascade that is unique to AD. These data suggest that the Aβ-mediated potentiation of tau uptake into cells should also be taken into account when designing Aβ-targeted therapeutics.

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

“…Several research groups studied tau-Aβ cross-seeding [219,220] and found that aggregated Aβ promoted the formation of tau aggregates. It was demonstrated that AβO enhances tau seeding in mouse neurons [221,222] and facilitates intracellular tau aggregation by promoting the uptake of tau seeds. However, transduced Aβ fibrils slightly reduce tau seeding.…”

Mitochondrial perturbation drives tau oligomers pathology in Alzheimer’s disease

“…These results indicate the contribution of mitochondrial ROS to tau oligomer formation and accumulation. Given that Aβ oligomers can seed and promote tau oligomerization and uptake of tau brils [25][26][27] , we propose that Aβ-mediated sustained mitochondrial stress and excessive ROS production could be a potential mechanism underlying Aβ-mediated/enhanced tau oligomers accumulation. Our studies suggest the role of the Aβ/ROS/mitochondria axis in aberrant tau oligomer accumulation, which links to cognitive dysfunction.…”

Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

“…Indeed, AβO have been shown to enhance, whereas Aβ fibrils reduce, the aggregation of tau (Shin et al 2019b). Furthermore, AβO promote the uptake of tau fibril seeds potentiating intracellular aggregation (Shin et al 2019a) and mediate neurite degeneration (Jin et al 2011). Mechanistic insights into this AβO-tau interaction arise from intriguing new data that demonstrate the involvement of NA, and α2 A adrenergic receptors (α2 A ARs) in mediating tau hyperphosphorylation and Alzheimer’s-related pathology in human and animal samples (Zhang et al 2020).…”