Sabec, M. H.; Adam, O.; Ashby, M. C.

Neurodegenerative tauopathies are associated with impairments in both active axonal trafficking and presynaptic function. Deficits in axonal trafficking reduce the supply of mitochondria to presynaptic sites, where they provide a local source of energy production and calcium homeostasis, and may therefore contribute to the progressive synaptic impairment. Using in vivo two-photon imaging of mitochondrial dynamics and axonal calcium activity in the PS19 mouse model of tauopathy, we show an age- and genotype-dependent decrease in mitochondrial trafficking which is correlated to disrupted presynaptic activity. Furthermore, we demonstrate a rescue in aberrant activity with pharmacological upregulation of axonal trafficking. The presented work reveals the disruptive influence of tau-induced trafficking impairments on presynaptic function in the early stages of the disease and highlights the therapeutic potential of targeting axonal trafficking as a strategy to confer synaptic resilience in a pathogenic environment.