Pharmacological restoration of deficits in mitochondrial trafficking rescues aberrant axonal activity in tauopathy
Sabec, M. H.; Adam, O.; Ashby, M. C.
Show abstract
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.
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