Format

Send to

Choose Destination
EMBO J. 2017 Nov 2;36(21):3120-3138. doi: 10.15252/embj.201797724. Epub 2017 Sep 1.

Somatodendritic accumulation of Tau in Alzheimer's disease is promoted by Fyn-mediated local protein translation.

Author information

1
Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Qld, Australia.
2
Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Qld, Australia j.goetz@uq.edu.au.

Abstract

The cause of protein accumulation in neurodegenerative disease is incompletely understood. In Alzheimer's disease (AD), the axonally enriched protein Tau forms hyperphosphorylated aggregates in the somatodendritic domain. Consequently, a process of subcellular relocalization driven by Tau phosphorylation and detachment from microtubules has been proposed. Here, we reveal an alternative mechanism of de novo protein synthesis of Tau and its hyperphosphorylation in the somatodendritic domain, induced by oligomeric amyloid-β (Aβ) and mediated by the kinase Fyn that activates the ERK/S6 signaling pathway. Activation of this pathway is demonstrated in a range of cellular systems, and in vivo in brains from Aβ-depositing, Aβ-injected, and Fyn-overexpressing mice with Tau accumulation. Both pharmacological inhibition and genetic deletion of Fyn abolish the Aβ-induced Tau overexpression via ERK/S6 suppression. Together, these findings present a more cogent mechanism of Tau aggregation in disease. They identify a prominent role for neuronal Fyn in integrating signal transduction pathways that lead to the somatodendritic accumulation of Tau in AD.

KEYWORDS:

Src kinase Fyn; amyloid‐β; microtubule‐associated protein Tau; protein synthesis; proximity ligation assay

PMID:
28864542
PMCID:
PMC5666608
DOI:
10.15252/embj.201797724
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center