High salt exposure promotes tau hyperphosphorylation and mitochondrial reverse electron transport associated neurodegeneration in Drosophila

The pathogenesis of neurodegenerative diseases like Alzheimer’s disease (AD) is complex and involves genetic as well as environmental factors. Previous studies have implicated dietary salt as a risk factor for both AD and cognitive impairment caused by vascular factors. The molecular mechanisms by which dietary salt contributes to cognitive impairment and AD remain poorly understood. Here we show that dietary high salt promotes tau hyperphosphorylation and mitochondrial dysfunction, two common features associated with AD and other age-related neurodegenerative diseases, in Drosophila . Hyperphosphorylated tau enters mitochondria and activates reverse electron transport (RET), results in elevated mitochondrial ROS and reduced NAD + /NADH ratio, proteostasis failure, neuronal loss, memory associated behavioral impairment, and shortened lifespan. The high salt effect on RET and lifespan is tau-dependent. Pharmacological or genetic inhibition of RET reduced tau hyperphosphorylation and rescued the cellular and organismal phenotypes caused by dietary high salt in a mitochondrial Sirtuin- and autophagy-dependent manner. These results suggest that tau phosphorylation and RET activation are physiological responses to high salt that become deregulated during chronic high salt exposure and contribute to neuronal dysfunction and degeneration. Our findings may offer molecular insight into how environmental factors impact the etiology of sporadic AD like conditions.