Journal
EMBO JOURNAL
Volume 36, Issue 21, Pages 3120-3138Publisher
WILEY
DOI: 10.15252/embj.201797724
Keywords
amyloid-beta; microtubule-associated protein Tau; protein synthesis; proximity ligation assay; Src kinase Fyn
Categories
Funding
- Estate of Dr Clem Jones AO
- State Government of Queensland
- Federal Government of Australia [ACT900116]
- Australian Research Council [DP130101932, LE130100078]
- National Health and Medical Research Council of Australia [GNT1037746, GNT1003150, GNT1127999]
- Australian Research Council [LE130100078] Funding Source: Australian Research Council
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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 nouo protein synthesis of Tau and its hyperphosphorylation in the somatodendritic domain, induced by oligomeric amyloid-beta (A beta) and mediated by the kinase Fyn that activates the ERKI/S6 signaling pathway. Activation of this pathway is demonstrated in a range of cellular systems, and in uiuo in brains from A beta-depositing, A beta-injected, and Fyn-overexpressing mice with Tau accumulation. Both pharmacological inhibition and genetic deletion of Fyn abolish the A beta-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.
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