The amyloid-? oligomer A?*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation.

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-? (A?) 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 A? from Tg2576 mice, which are a model for AD. We found that A?*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, A?*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 II? (CaMKII?). In cultured neurons and in the brains of Tg2576 mice, activated CaMKII? 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 A? forms (dimers and trimers) did not trigger these effects. Our results indicate that distinct A? 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.

SUBMITTER: Amar F 

PROVIDER: S-EPMC5859319 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature