Pharmacological restoration of deficits in mitochondrial trafficking rescues aberrant axonal activity in tauopathy

Abstract

Neurodegenerative tauopathy is associated with impairments in both active axonal trafficking and presynaptic function. Although deficits in axonal trafficking reduce supply of mitochondria to presynaptic sites, where they provide a local source of energy production and calcium homeostasis, it is unclear if this contributes to progressive synaptic impairment driven by aberrant tau. Our in vivo two-photon imaging of mitochondrial movement and calcium dynamics in neocortical neurons of tauopathy mice revealed a progressive tau-driven decrease in axonal mitochondrial trafficking that correlates with disruption of presynaptic activity. Furthermore, we have shown that tau-driven presynaptic dysfunction can be rescued by pharmacological upregulation of axonal mitochondrial trafficking. Therefore, as well as revealing the disruptive influence of tau-induced mitochondrial trafficking impairments on presynaptic function in early stages of tauopathy, these findings highlight the therapeutic potential of targeting axonal trafficking to confer synaptic resilience to pathology.