Amyloid Beta-Mediated KIF5A Deficiency Disrupts Anterograde Axonal Mitochondrial Movement



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Academic Press Inc.


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. © 2019 Elsevier Inc.


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Alzheimer's disease, Amyloid beta-protein, Kinesin heavy chain isoform 5A, Kinesin, Lentiviruses, Autopsy, Cell migration, Cells—Motility, Protein deficiency, Temporal lobes

National NaturalScience Foundation of China (31271145, 81200847, 81771153),Natural Science Foundation of Shandong Province (JQ201318), KeyResearch and Development Program of Shandong Province(2018GSF121003), Alzheimer's Association (NIRG-12-242803, AARG-16-442863), and China Scholarship Council (201706220265)


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