Research ArticleAlzheimer’s Disease

The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation

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Sci. Signal.  09 May 2017:
Vol. 10, Issue 478, eaal2021
DOI: 10.1126/scisignal.aal2021

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A more pathological amyloid-β oligomer

Amyloid-β (Aβ) is implicated in the pathology of Alzheimer’s disease (AD), and various types of Aβ oligomers emerge at different stages of AD. Aβ promotes the modification and aggregation of the microtubule-associated protein tau, which is associated with neuronal toxicity and impaired cognition in various neurodegenerative disorders. Using several transgenic mouse models of AD and cultured cortical neurons, Amar et al. found that the 56-kDa oligomer Aβ*56, but not Aβ dimers or trimers, stimulated an influx in intracellular Ca2+ that triggered phosphorylation of tau at a site that promoted its aggregation. The findings link a specific amyloid form to tau pathology and suggest that dissecting the molecular and stage-specific roles of Aβ oligomers may lead to improved therapies.

Abstract

Oligomeric forms of amyloid-forming proteins are believed to be the principal initiating bioactive species in many neurodegenerative disorders, including Alzheimer’s disease (AD). Amyloid-β (Aβ) oligomers are implicated in AD-associated phosphorylation and aggregation of the microtubule-associated protein tau. To investigate the specific molecular pathways activated by different assemblies, we isolated various forms of Aβ from Tg2576 mice, which are a model for AD. We found that Aβ*56, a 56-kDa oligomer that is detected before patients develop overt signs of AD, induced specific changes in neuronal signaling. In primary cortical neurons, Aβ*56 interacted with N-methyl-d-aspartate receptors (NMDARs), increased NMDAR-dependent Ca2+ influx, and consequently increased intracellular calcium concentrations and the activation of Ca2+-dependent calmodulin kinase IIα (CaMKIIα). In cultured neurons and in the brains of Tg2576 mice, activated CaMKIIα was associated with increased site-specific phosphorylation and missorting of tau, both of which are associated with AD pathology. In contrast, exposure of cultured primary cortical neurons to other oligomeric Aβ forms (dimers and trimers) did not trigger these effects. Our results indicate that distinct Aβ assemblies activate neuronal signaling pathways in a selective manner and that dissecting the molecular events caused by each oligomer may inform more effective therapeutic strategies.

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