%0 Journal Article
%T Amyloid beta-mediated KIF5A deficiency disrupts anterograde axonal mitochondrial movement.
%A Wang Q
%A Tian J
%A Chen H
%A Du H
%A Guo L
%J Neurobiol Dis
%V 127
%N 0
%D 07 2019
%M 30923004
%F 7.046
%R 10.1016/j.nbd.2019.03.021
%X Mitochondria are crucial organelles for neurophysiology and brain mitochondrial defects constitute a characteristic of Alzheimer's disease (AD). Impaired axonal mitochondrial traffic, especially the anterograde axonal mitochondrial transport is a pronouncing mitochondrial defect that underlies synaptic failure in AD-related conditions. However, the detailed molecular mechanisms of such axonal mitochondrial abnormality have not been fully understood. KIF5A is a key isoform of kinesin-1, which is a key molecular machinery in facilitating anterograde axonal mitochondrial transport. In this study, we have determined a downregulation of KIF5A in postmortem AD temporal lobes. Further experiments on amyloid beta (Aβ)-treated primary neuron culture and 5 × FAD mice suggest a close association of Aβ toxicity and KIF5A loss. Downregulation of KIF5A mimics Aβ-induced axonal mitochondrial transport deficits, indicating a potential role of KIF5A deficiency in AD-relevant axonal mitochondrial traffic abnormalities. Importantly, the restoration of KIF5A corrects Aβ-induced impairments in axonal mitochondrial transport, especially the anterograde traffic, with little or no impact on retrograde axonal mitochondrial motility. Our findings suggest a novel KIF5A-associated mechanism conferring Aβ toxicity to axonal mitochondrial deficits. Furthermore, the results implicate a potential therapeutic avenue by protecting KIF5A function for the treatment of AD.