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An AMPK-dependent regulatory pathway in tau-mediated toxicity
Alessia Galasso1, Charles S Cameron2, Bruno G Frenguelli2
1School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK alessia.galasso@path.ox.ac.uk.
Biology Open
|August 16, 2017
Summary
AMPK activation in neurodegenerative tauopathies exacerbates tau toxicity by increasing tau phosphorylation without activating autophagy. Stimulating autophagy with rapamycin can reduce this toxicity, suggesting combination therapies.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Neurodegenerative tauopathies involve hyperphosphorylated tau aggregates.
- 5'AMP-activated protein kinase (AMPK) is involved in metabolism, tau phosphorylation, and autophagy.
- AMPK's role in tauopathies is unclear, potentially being neurotoxic or neuroprotective.
Purpose of the Study:
- To investigate the impact of AMPK and autophagy on tau-mediated toxicity in vivo.
- To analyze the consequences of AMPK activation without autophagy enhancement in tauopathies.
- To explore therapeutic strategies targeting tau phosphorylation and autophagy.
Main Methods:
- Utilized a Drosophila in vivo quantitative model.
- Recapitulated AMPK-mediated tauopathy with increased tau phosphorylation and impaired autophagy.
- Assessed the effect of AMPK binding and phosphorylation of tau at Ser-262.
Main Results:
- AMPK phosphorylates tau at Ser-262, hindering its degradation and exacerbating toxicity.
- This exacerbated tau toxicity was ameliorated by rapamycin-induced autophagy stimulation.
- Demonstrated a condition of increased tau phosphorylation without corresponding autophagy activation.
Conclusions:
- AMPK-mediated tau phosphorylation at Ser-262 contributes to tau toxicity in tauopathies.
- Combinatorial therapies targeting tau phosphorylation and AMPK-independent autophagy induction are promising.
- The developed Drosophila model serves as a valuable tool for screening drugs that enhance autophagy.
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