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Sci Signal. 2017 May 9;10(478). pii: eaal2021. doi: 10.1126/scisignal.aal2021.

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

Amar F1,2,3, Sherman MA1,2,3, Rush T4, Larson M1,2,3, Boyle G1,2,3, Chang L5, Götz J6, Buisson A4, Lesné SE7,2,3.

Author information

1
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55414, USA.
2
N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN 55414, USA.
3
Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55414, USA.
4
INSERM, U1216, Université Grenoble Alpes, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042, France.
5
Sydney Medical School, Brain and Mind Research Institute, University of Sydney, Camperdown, Sydney, New South Wales 2050, Australia.
6
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia.
7
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55414, USA. lesne002@umn.edu.

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.

PMID:
28487416
PMCID:
PMC5859319
DOI:
10.1126/scisignal.aal2021
[Indexed for MEDLINE]
Free PMC Article

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