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An AMPK-dependent regulatory pathway in tau-mediated toxicity

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Galasso, Alessia, Cameron, Charles S., Frenguelli, Bruno G. and Moffat, Kevin G. (2017) An AMPK-dependent regulatory pathway in tau-mediated toxicity. Biology Open, 6 (10). pp. 1434-1444. doi:10.1242/bio.022863

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Official URL: http://dx.doi.org/10.1242/bio.022863

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Abstract

Neurodegenerative tauopathies are characterized by accumulation of hyperphosphorylated tau aggregates primarily degraded by autophagy.

The 5'AMP-activated protein kinase (AMPK) is expressed in most cells, including neurons. Alongside its metabolic functions, it is also known to be activated in Alzheimer's brains, phosphorylate tau and be a critical autophagy activator. Whether it plays a neurotoxic or neuroprotective role remains unclear. Complexly in tauopathies, while stress conditions can result in AMPK activation enhancing tau-mediated toxicity, AMPK activation is not always concomitant with autophagic induction.

Using a Drosophila in vivo quantitative approach, we have analysed the impact of AMPK and autophagy on tau-mediated toxicity, recapitulating the AMPK-mediated tauopathy condition: increased tau phosphorylation, without corresponding autophagy activation.

We have demonstrated that AMPK, binding to and phosphorylating tau at Ser-262, a site reported to facilitate soluble tau accumulation, affects its degradation. This phosphorylation results in exacerbation of tau toxicity and is ameliorated via rapamycin-induced autophagy stimulation.

Our findings support the development of combinatorial therapies effective at reducing tau toxicity targeting tau phosphorylation and AMPK-independent autophagic induction. The proposed in vivo tool represents an ideal readout to perform preliminary screening for drugs promoting this process.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
Divisions: Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Protein kinases, Microtubules, Drosophila, Cell death, Phosphorylation
Journal or Publication Title: Biology Open
Publisher: The Company of Biologists Ltd.
ISSN: 2046-6390
Official Date: 15 October 2017
Dates:
DateEvent
15 October 2017Published
14 August 2017Available
8 August 2017Accepted
Volume: 6
Number: 10
Page Range: pp. 1434-1444
DOI: 10.1242/bio.022863
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
Funder: National Centre for the Replacement, Refinement, and Reduction of Animals in Research (Great Britain) (NC3R)
Grant number: G0900801/91180 (NC3R)

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