Familial Alzheimer disease mutation undermines axonal transportby enhancing dynactin recruitment to the APP motor assemblies

Stokin, G. B.; Feole, M.

doi:10.1101/2022.11.17.516829

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Familial Alzheimer disease mutation undermines axonal transportby enhancing dynactin recruitment to the APP motor assemblies

Stokin, G. B.·Feole, M.

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Abstract

Experiments in flies, mice and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimers disease (AD), however, the underlying mechanisms remain unknown1,2. We report that the Swedish familial AD (FAD) mutation perturbs fast anterograde axonal transport of the amyloid precursor protein (APP) by altering directionality of its movement. APP thus spends more time in retrograde movement and accumulates in the soma. We found that the Swedish mutation enhances recruitment of dynactin 1 to the APP transport assemblies. Given that dynactin 1 activates the retrograde motor dynein3, this hampers physiological anterograde axonal transport of APP. We last show that the Swedish mutation perturbs also the axonal transport of early endosomes, which rely on the same molecular motors as APP. Our findings reveal extensive impairment of the axonal transport pathways by a FAD mutation, which reflects dysregulation of the cargo motor assemblies.

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Stokin, G. B., Feole, M.. 2022-11-18. Familial Alzheimer disease mutation undermines axonal transportby enhancing dynactin recruitment to the APP motor assemblies. https://doi.org/10.1101/2022.11.17.516829

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