Amyloid-beta-derived diffusible ligands cause impaired axonal transport of mitochondria in neurons

Abstract

Background: Alzheimer's disease (AD) is the most prevalent form of dementia predominantly affecting the elderly. It is believed that soluble amyloid-beta (Abeta) oligomers are involved in the pathogenesis of AD, yet the underlying mechanisms remain elusive.

Objectives: Emerging evidence suggests that mitochondrial dysfunction likely plays a critical role in Abeta-induced neuronal degeneration. Previously, we demonstrated that Abeta-derived diffusible ligands (ADDLs) induce reduced mitochondrial density in neurites, and we suspect that an impaired mitochondrial trafficking might be involved, which is tested in this study.

Methods: Using live cell imaging, anterograde and retrograde transport of mitochondria in primary hippocampal neurons treated with sub-lethal doses of ADDLs was measured.

Results: We found that ADDLs induced significant impairment in both anterograde and retrograde transport of mitochondria along axons.

Conclusion: These results suggest that an impaired mitochondrial transport likely contributes to ADDL-induced abnormal mitochondrial distribution and dysfunction and also reinforce the idea that axonal transport is likely involved in AD pathogenesis.

Fig. 1

Effect of ADDLs on FAT of mitochondria. Rat E18 hippocampal neurons (DIV 9) were transfected with Mito-DsRed2. 24 h after incubation with or without 800 n M ADDLs at DIV 11, neurons were imaged in time-lapse (10 s interval, 20 min). a Representative kymographs showing transport of mitochondria in the segment of axon around 100 μm in length beginning 300 μm from the cell body of control neurons or neurons treated with Aβ42–1 and ADDLs. b Quantification of mitochondria flux (number mitochondria/10 min) revealed that both anterograde and retrograde FAT of mitochondria were greatly impaired by ADDLs rather than negative control or Aβ42–1. At least 20 neurons were analyzed in three independent experiments (∗ p ≤ 0.05, Student's t test).