Increased HSC70‐4/HSPA8 regulated autophagy reduces tau‐mediated synaptic dysfunction

Background Tau tangles are present in the brains of Alzheimer diseased (AD) patients and strategies that remove Tau oligomers and Tau tangles are tested in clinical trials. These anti‐Tau drugs may keep misfolded Tau from spreading and damaging additional neurons, but they may be inefficient at targeting soluble Tau early in the disease before tangles are formed and thus be relatively late to spare cognitive defects. Our research is therefore refreshing as it may tackle early Tau induced dysfunction. We have shown in Drosophila that the overexpression of the chaperone Hsc70‐4 promotes endosomal microautophagy at presynapses and regulates the turnover of synaptic proteins harboring pentapeptide motifs, biochemically related to the KFERQ sequence (Uytterhoeven, 2015). Intriguingly, Tau harbors two such motifs. Method We tested if increasing endosomal microautophagy by overexpressing Hsc70‐4 has an effect on Tau‐mediated synaptic defects . Result Indeed, increasing microautophagy reduces presynaptic Tau levels and presynaptic vesicle sequestrations at presynapses, two phenotypes previously shown by our lab to appear after expressing pathogenic Tau in the fly nervous system (Zhou, 2017 and McInnes, 2018). In addition, via lentiviral‐mediated overexpression of HSPA8, the human homologue of Hsc70‐4, we are able to increase HSPA8 regulated autophagy in human neurons. Conclusion Together, our work provides important molecular insight into the contribution of Hsc70‐4/HSPA8 regulated autophagy on AD disease onset and progression and may contribute to the development of methods and treatments to alleviate the defects in dementia.