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bioRxiv · 10.1101/2025.05.02.651902

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

Sabec, M. H.·Adam, O.·Ashby, M. C.
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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.

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Sabec, M. H., Adam, O., Ashby, M. C.. 2025-05-05. Pharmacological restoration of deficits in mitochondrial trafficking rescues aberrant axonal activity in tauopathy. https://doi.org/10.1101/2025.05.02.651902

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