Mitochondrial Mislocalization Underlies Aβ42-Induced Neuronal Dysfunction in a Drosophila Model of Alzheimer's Disease

Abstract

The amyloid-β 42 (Aβ42) is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which Aβ42 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 Aβ42 induces mitochondrial mislocalization, which contributes to Aβ42-induced neuronal dysfunction in a transgenic Drosophila model. In the Aβ42 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. Aβ42-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 Aβ42 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 Aβ42-induced neuronal dysfunction. These results demonstrate that mislocalization of mitochondria underlies the pathogenic effects of Aβ42 in vivo.

Effects of Chlorpyrifos and Chlorpyrifos-Oxon on the Dynamics and Movement of Mitochondria in Rat Cortical Neurons

“…From a pathophysiological standpoint, it is important to note that axonal transport deficits and a decreased ability of mitochondria to meet the spatial and local transient demands of the cell can compromise neuronal function and promote programmed cell death (Chang and Reynolds, 2006;Chen and Chan, 2006;Iijima-Ando et al, 2009). Although no causal connections can be made at this time, it also is interesting to note (given the results of our experiments) that occupational exposures to OP-pesticides have recently been associated with an increased risk for developing Alzheimer's disease (Hayden et al, 2010).…”

Mitochondrial regulation of epigenetics and its role in human diseases

“…86,87 Mitochondrial dysfunction has been associated with the occurrence of certain cancers 5,88,89 and neurodegenerative disorders, 80 including Alzheimer disease. 90 Increasing evidence has shown there to be an interdependent relationship between the mitochondria and the nuclear genome, including DNA methylation in both the nucleus and the mitochondrial matrix. 5,6,33,89 An understanding of the role these factors might have in regulating nuclear DNA encoded mitochondrial genes is of keen interest.…”

“…Effectors may include transcription factors, 12 involved in regulation of cell cycle, DNA repair and apoptosis. Identifying the epigenetic profile of tissue-dependent differentially methylated regions of genes and their possible perturbed state in mitochondrial diseases, 107 neurological disorders 79,80,90 and cancers 6 could further our understanding of the pathogenesis of complex human diseases due to defective mitochondria. damage has been associated with a mitochondrial damage checkpoint (mitocheckpoint).…”

Impact of Sustained Exposure to β-Amyloid on Calcium Homeostasis and Neuronal Integrity in Model Nerve Cell System Expressing α4β2 Nicotinic Acetylcholine Receptors

“…A␤ may also affect mitochondrial dynamics (fission/fusion equilibrium) and distribution in the axon and synapse. Recent studies using an in vivo fly model overexpressing A␤ showed that depletion of presynaptic and axonal mitochondria was one of the earliest detectable deficits, preceding A␤-induced presynaptic deficits in motor function (34,35). A␤-induced mitochondrial mislocalization was also confirmed in hippocampal neurons (36).…”