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Author Notes:

Correspondence: james.zheng@emory.edu

YR designed and performed all the experiments and drafted the manuscript.

JQZ oversaw and guided the study and wrote the manuscript together with YR.

Both authors read and approved the final manuscript.

We would like to thank Drs. Jason Fritz and Marla Gearing at Emory CND for their help with human tissue samples.

We also thank Dr. Stuart L. Schreiber from Howard Hughes Medical Institute for providing us the specific HDAC6 inhibitor tubacin.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

This research was supported in part by grants from the National Institutes of Health (GM083889 and MH104632), a pilot grant from Emory Alzheimer’s Disease Resource Center (ADRC P50 AG025688), a NINDS core facilities grant (P30NS055077) to the Neuronal Imaging Core of Emory Neuroscience, and a postdoctoral fellowship from the Ellison Medical Foundation/American Federation for Aging Research to YR.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • Alzheimer's disease
  • Transport
  • Fragmentation
  • Hippocampus
  • HDAC6
  • Drp-1
  • GSK3 beta
  • CULTURED HIPPOCAMPAL-NEURONS
  • ALZHEIMERS-DISEASE
  • AXONAL-TRANSPORT
  • NEURODEGENERATIVE DISEASES
  • ALPHA-TUBULIN
  • DRP1 PHOSPHORYLATION
  • TRAFFICKING
  • ACETYLATION
  • SYNAPSES

Amyloid beta oligomers elicit mitochondrial transport defects and fragmentation in a time-dependent and pathway-specific manner

Tools:

Journal Title:

Molecular Brain

Volume:

Volume 9, Number 1

Publisher:

, Pages 79-79

Type of Work:

Article | Final Publisher PDF

Abstract:

Small oligomeric forms of amyloid-β (Aβ) are believed to be the culprit for declined brain functions in AD in part through their impairment of neuronal trafficking and synaptic functions. However, the precise cellular actions of Aβ oligomers and underlying mechanisms in neurons remain to be fully defined. Previous studies have identified mitochondria as a major target of Aβ toxicity contributing to early cognitive decline and memory loss in neurodegenerative diseases including Alzheimer's disease (AD). In this study, we report that Aβ oligomers acutely elicit distinct effects on the transport and integrity of mitochondria. We found that acute exposure of hippocampal neurons to Aβ oligomers from either synthetic peptides or AD brain homogenates selectively impaired fast transport of mitochondria without affecting the movement of late endosomes and lysosomes. Extended exposure of hipoocampal neurons to Aβ oligomers was found to result in mitochondrial fragmentation. While both mitochondrial effects induced by Aβ oligomers can be abolished by the inhibition of GSK3β, they appear to be independent from each other. Aβ oligomers impaired mitochondrial transport through HDAC6 activation whereas the fragmentation involved the GTPase Drp-1. These results show that Aβ oligomers can acutely disrupt mitochondrial transport and integrity in a time-dependent and pathway-specific manner. These findings thus provide new insights into Aβ-induced mitochondrial defects that may contribute to neuronal dysfunction and AD pathogenesis.

Copyright information:

© 2016 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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