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Amyloid beta-mediated KIF5A deficiency disrupts anterograde axonal mitochondrial movement

Qi Wang1, Jing Tian2, Hao Chen2

  • 1AD Center, Department of Neurology, Qianfoshan Hospital Affiliated to Shandong University, Jinan, Shandong 250014, China; Department of Biological Sciences, The University of Texas at Dallas, 800 W. Campbell Road, Richardson, TX 75080, USA.

Neurobiology of Disease
|March 30, 2019
PubMed

Insights

Alzheimer's disease (AD) involves mitochondrial transport defects. This study reveals amyloid beta toxicity reduces KIF5A, a motor protein crucial for mitochondrial transport, suggesting KIF5A protection as a potential AD therapy.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Mitochondrial Biology

Background:

  • Mitochondrial dysfunction is a hallmark of Alzheimer's disease (AD).
  • Impaired axonal transport of mitochondria, particularly anterograde transport, contributes to synaptic failure in AD.
  • The precise molecular mechanisms underlying these mitochondrial transport deficits remain unclear.

Purpose of the Study:

  • To investigate the role of KIF5A, a kinesin-1 motor protein, in Alzheimer's disease-related axonal mitochondrial transport.
  • To elucidate the association between amyloid beta (Aβ) toxicity and KIF5A downregulation in AD.
  • To explore the therapeutic potential of restoring KIF5A function in AD.

Main Methods:

  • Analysis of KIF5A levels in postmortem AD temporal lobes.
  • Experiments using amyloid beta (Aβ)-treated primary neuron cultures.
  • Studies involving 5×FAD transgenic mouse models of AD.

Main Results:

  • KIF5A was found to be downregulated in postmortem AD brain tissue.
  • Aβ toxicity was closely associated with KIF5A loss in neuronal cultures and AD mouse models.
  • KIF5A deficiency mimicked Aβ-induced anterograde axonal mitochondrial transport deficits.
  • Restoring KIF5A levels ameliorated Aβ-induced mitochondrial transport impairments, especially anterograde transport.

Conclusions:

  • A novel mechanism links Aβ toxicity to axonal mitochondrial deficits via KIF5A downregulation.
  • KIF5A deficiency plays a significant role in AD-associated axonal mitochondrial transport abnormalities.
  • Protecting KIF5A function represents a potential therapeutic strategy for Alzheimer's disease.
Keywords:
Alzheimer's diseaseAmyloid betaAnterograde transportAxonal mitochondrial motilityKIF5A

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