Mitochondrial mislocalization underlies Ab42-induced neuronal dysfunction in a drosophila model of alzheimer's disease

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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URL: http://www.ncbi.nlm.nih.gov/pubmed/20016833
DOI: 10.1371/journal.pone.0008310

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: http://repository.cshl.edu/id/eprint/27414

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