Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease

The amyloid-b 42 (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. Citation: Iijima-Ando K, Hearn SA, Shenton C, Gatt A, Zhao L, et al. (2009) Mitochondrial Mislocalization Underlies Ab42-Induced Neuronal Dysfunction in a Drosophila Model of Alzheimer’s Disease. PLoS ONE 4(12): e8310. doi:10.1371/journal.pone.0008310 Editor: Mel B. Feany, Brigham and Women’s Hospital/Harvard Medical School, United States of America Received October 9, 2009; Accepted November 21, 2009; Published December 15, 2009 Copyright: 2009 Iijima-Ando et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by start-up funds from the Farber Institute for Neurosciences, a pilot research grant from the Thomas Jefferson University, and grants from The Gilbert Foundation, the American Federation for Aging Research (http://www.afar.org/), the Alzheimer’s Association (http://www.alz.org/ index.asp) (NIRG-08-91985) and the National Institutes of Health (R01AG032279-A1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] (KIA); [email protected] (KI)