5-ALA/SFC Mitigates Tau Toxicity via Lowering Oxidative Stress in a Drosophila Model of Tau Toxicity

Mitochondrial dysfunctions contribute to the pathogenesis of tauopathies, a group of neurodegenerative diseases with abnormal accumulation of microtubule-associated protein tau. The combination of 5-aminolevulinic acid (5-ALA) and sodium ferrous citrate (SFC) is known to improve mitochondrial functions. Here, we report that 5-ALA combined with SFC (5-ALA/SFC) improves mitochondrial functions and mitigates neurodegeneration in transgenic Drosophila expressing human tau. We found that tau reduces ATP levels, decreases mitochondrial distribution to neurites, and increases mitochondrial reactive oxygen species (ROS). Expression of oxidative phosphorylation (OXPHOS) genes was upregulated, and activities of complexes I and IV were elevated. Feeding 5-ALA/SFC to tau flies lowers oxidative damage without correcting OXPHOS activities or mitochondrial distribution. 5-ALA/SFC treatment suppressed pathological tau phosphorylation and mitigated tau-induced neurodegeneration. These results suggest that 5-ALA/SFC attenuates a neurodegenerative pathway involving tau, mitochondria, and ROS.