The pathogenic mutation in tau defines the route of tau accumulation at presynapses.

Abstract

Tau's primary localization is in the axons of neurons. At axons, Tau binds microtubuli and stabilizes them. Many of the pathogenic mutations interfere with binding of Tau to the microtubuli resulting in the relocation of Tau to different neuronal compartments, including the presynapse. Our lab has shown that Tau interact with synaptic vesicles via the synaptic vesicle protein, Synaptogyrin-3 and excessive Tau levels at presynapses results in the sequestration of synaptic vesicles compromising neurotransmission in Tau mutant fly and primary mouse neurons (Zhou, Nat. Commun. 2017; McInnes, Neuron, 2018). In addition, lowering Synaptogyrin-3 expression in TauP301L mutant mice reduces Tau-synaptic vesicle interactions and rescues Tau-mediated memory defects and synapse loss in these mice (Largo-Barrientos,Neuron, 2021). Although, the interaction of Tau with synaptic vesicles is reduced with lowering Synaptogyrin-3 expression, Tau continues to accumulate at presynapses. To reduce Tau levels and keep the presynapse healthy over time, we increased endosomal microautophagy by the expression of Hsc70-4 (Uytterhoeven, Neuron, 2015) in Tau mutant fly neurons . Despite, the overall reduced activity of degradation pathways in pathogenic conditions, we were able to reduce presynaptic TauP301L levels and restore reduced synaptic vesicle mobility and neurotransmission by increasing endosomal microautophagy. However, increasing endosomal microautophagy is not effective in lowering pathogenic TauV337M . Using a fluorescent timer attached to Tau, we show that older Tau is present in TauV337M compared to TauP301L mutant presynapses indicating that the turnover of TauV337M is hindered. On the contrary, with a fluorescence recovery after photobleaching assay we show that TauP301L is more mobile in axons compared to TauV337M indicating that TauP301L detaches more easily from the microtubuli. Together, these data show that both the detachment of Tau from microtubuli and defective turnover of Tau at presynapses contribute to the accumulation of Tau at presynapses and depending on the pathogenic mutation one of the two pathways plays a more prominent role in the accumulation of Tau at presynapses. Hence, these observations have further implications in the development of new therapies acting on Tau.