Amyloid ß-protein oligomers promote the uptake of tau fibril seeds potentiating intracellular tau aggregation.
Alzheimers Res Ther
; 11(1): 86, 2019 10 18.
Article
en En
| MEDLINE
| ID: mdl-31627745
ABSTRACT
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-ß (Aß) 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 Aß potentiates intracellular tau aggregation, and show that oligomeric Aß specifically exacerbates proteopathic seeding by tau. Using tau-biosensor cells, we show that treatment with sub-toxic concentrations of Aß oligomers, but not monomers or fibrils, "primes" cells, making them more susceptible to tau seeding. The treatment with Aß 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 Aß-oligomer priming.RESULTS:
Priming by Aß oligomers appears to be specific to tau, as α-synuclein seeding is unaffected by this treatment. Aß oligomer-enhanced tau seeding also occurs in primary mouse neurons and human neuroblastoma cells. Using fluorescently labeled tau seeds, we find that treatment with Aß oligomers significantly enhances the cellular uptake of tau seeds, whereas a known tau-uptake inhibitor blocks the effect of Aß on tau uptake.CONCLUSION:
The ability of Aß to promote tau seeding suggests a specific and plausible mechanism by which extracellular Aß initiates a deleterious cascade that is unique to AD. These data suggest that the Aß-mediated potentiation of tau uptake into cells should also be taken into account when designing Aß-targeted therapeutics.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Encéfalo
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Péptidos beta-Amiloides
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Proteínas tau
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Enfermedad de Alzheimer
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Neuronas
Límite:
Humans
Idioma:
En
Revista:
Alzheimers Res Ther
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos