An AMPK-dependent regulatory pathway in tau-mediated toxicity.

Neurodegenerative tauopathies are characterised 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. In tauopathies stress conditions can result in AMPK activation, enhancing tau-mediated toxicity. Paradoxically, in these cases AMPK activation does not always lead to protective autophagic responses. Using a 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 tool represents an ideal readout to perform preliminary screening for drugs promoting this process.