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Drp1/Fis1 interaction mediates mitochondrial dysfunction, bioenergetic failure and cognitive decline in Alzheimer's

Amit U Joshi1, Nay L Saw2, Mehrdad Shamloo2

  • 1Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Oncotarget
|February 22, 2018
PubMed

Insights

Targeting excessive mitochondrial fission by inhibiting Drp1/Fis1 interaction may treat Alzheimer's disease (AD). This approach reduced Aβ accumulation and improved cognitive function in AD models, suggesting a new therapeutic strategy for AD patients.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Mitochondrial Biology

Background:

  • Mitochondrial dynamics, regulated by fusion and fission, are crucial for cellular health.
  • Mitochondrial dysfunction is increasingly implicated in the pathogenesis of Alzheimer's disease (AD).
  • Drp1-mediated mitochondrial fission is a key process affected in neurodegenerative conditions.

Purpose of the Study:

  • To investigate the role of Drp1/Fis1 interaction in Alzheimer's disease.
  • To evaluate the therapeutic potential of inhibiting Drp1/Fis1 interaction in AD models.

Main Methods:

  • Assessed Drp1/Fis1 interaction in Aβ-treated neurons and AD patient fibroblasts.
  • Utilized P110 peptide to specifically inhibit Drp1/Fis1 interaction.
  • Evaluated mitochondrial function, Aβ accumulation, and cognitive deficits in cell and mouse models of AD.

Main Results:

  • Increased Drp1/Fis1 interaction was observed in AD models.
  • P110 treatment attenuated Aβ-induced mitochondrial dysfunction and protected neurons.
  • Inhibition of Drp1/Fis1 interaction improved behavioral deficits and reduced neuropathology in 5XFAD mice.

Conclusions:

  • Excessive Drp1/Fis1-mediated mitochondrial fission contributes significantly to AD neuropathology and cognitive decline.
  • Targeting the Drp1/Fis1 interaction represents a promising therapeutic strategy for Alzheimer's disease.
  • Modulating mitochondrial dynamics offers a novel avenue for AD treatment.
Keywords:
Alzheimer’s diseaseDrp1P110mitochondrial dysfunctionpatient-derived fibroblasts

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