Iijima-Ando, K., Hearn, S. A., Shenton, C., Gatt, A., Zhao, L., Iijima, K. (2009) Mitochondrial mislocalization underlies Ab42-induced neuronal dysfunction in a drosophila model of alzheimer's disease. PLoS ONE, 4 (12). pp. 1-13.
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Abstract
The amyloid-b42 (Ab42) is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which Ab42 induces neuronal dysfunction and degeneration remain elusive. Mitochondrial dysfunctions are implicated in AD brains. Whether mitochondrial dysfunctions are merely a consequence of AD pathology, or are early seminal events in AD pathogenesis remains to be determined. Here, we show that Ab42 induces mitochondrial mislocalization, which contributes to Ab42-induced neuronal dysfunction in a transgenic Drosophila model. In the Ab42 fly brain, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial damage or neurodegeneration. In contrast, organization of microtubule or global axonal transport was not significantly altered at this stage. Ab42-induced behavioral defects were exacerbated by genetic reductions in mitochondrial transport, and were modulated by cAMP levels and PKA activity. Levels of putative PKA substrate phosphoproteins were reduced in the Ab42 fly brains. Importantly, perturbations in mitochondrial transport in neurons were sufficient to disrupt PKA signaling and induce late-onset behavioral deficits, suggesting a mechanism whereby mitochondrial mislocalization contributes to Ab42-induced neuronal dysfunction. These results demonstrate that mislocalization of mitochondria underlies the pathogenic effects of Ab42 in vivo. © 2009 Iijima-Ando et al.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > mental disorders > delirium dementia cognitive disorders > Alzheimer's disease diseases & disorders > mental disorders > delirium dementia cognitive disorders diseases & disorders organism description > animal > insect > Drosophila diseases & disorders > mental disorders organism description > animal > insect organs, tissues, organelles, cell types and functions > organelles, types and functions > mitochondria organs, tissues, organelles, cell types and functions > organelles, types and functions organs, tissues, organelles, cell types and functions |
| CSHL Authors: | |
| Communities: | CSHL labs |
| Depositing User: | Matt Covey |
| Date: | 2009 |
| Date Deposited: | 20 Feb 2013 21:20 |
| Last Modified: | 20 Feb 2013 21:20 |
| PMCID: | PMC2790372 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27414 |
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