Mitochondrial Mislocalization Underlies A beta 42-Induced Neuronal Dysfunction in a Drosophila Model of Alzheimer's Disease

作者：Iijima Ando Kanae^*; Hearn Stephen A; Shenton Christopher; Gatt Anthony; Zhao LiJuan; Iijima Koichi

来源：PLos One, 2009, 4(12): e8310.

DOI：10.1371/journal.pone.0008310

The amyloid-beta 42 (A beta 42) is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which A beta 42 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 A beta 42 induces mitochondrial mislocalization, which contributes to A beta 42-induced neuronal dysfunction in a transgenic Drosophila model. In the A beta 42 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. A beta 42-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 A beta 42 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 A beta 42-induced neuronal dysfunction. These results demonstrate that mislocalization of mitochondria underlies the pathogenic effects of A beta 42 in vivo.

• 出版日期2009-12-15