. Expression of beta-amyloid induced age-dependent presynaptic and axonal changes in Drosophila. J Neurosci. 2010 Jan 27;30(4):1512-22. PubMed.

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  1. We thank Dr. Zhu for citing our work (Iijima-Ando et al., 2009) in his comment. In our Aβ42 fly brain neurons, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial damage or neurodegeneration. At this stage, organization of microtubules and distribution of synaptic vesicle markers were not significantly altered, suggesting that mitochondrial mislocalization occurs without global axonal transport defects.

    By knocking down milton, an adaptor protein that links mitochondria and kinesin, we showed that reduction in mitochondria transport exacerbated Aβ42-induced behavioral defects. Furthermore, milton knockdown by itself caused neuronal dysfunction at a later stage. Our results indicate that Aβ42-induced mitochondrial mislocalization contributes to Aβ42-induced neuronal dysfunction in vivo.

    References:

    . Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease. PLoS One. 2009;4(12):e8310. PubMed.

    View all comments by Kanae Ando
  2. The authors described a new system to examine the effect of Aβ on neuronal morphogenesis and physiology in the adult fly brain. They observed depletion of mitochondria in neuronal processes in aged brain. Although the authors raised the possibility of mitochondrial fission defects induced by Aβ as a possible cause, it is pure speculation at this point. It could simply be caused by damage of mitochondria by Aβ and subsequent removal of abnormal mitochondria. An earlier study published in PNAS (Wang et al., 2008) provided more convincing evidence linking Aβ to mitochondrial fission/fusion defects in mammalian hippocampal neurons.

    References:

    . Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23. PubMed.

  3. For mitochondrial effects in AD please see our Pharmacogenomics Journal article published in 2009. localizing a variable polyT mutation in the translocase of the outer mitochondrial membrane as a diagnostic predictor of risk for AD.

    View all comments by Allen Roses
  4. Synaptic loss and mitochondrial dysfunction are both early features of Alzheimer disease, and connecting the two, as demonstrated in several recent studies including this present work, is attractive. Our recent work revealed that mitochondria accumulate in the soma and are reduced in neuronal processes in AD pyramidal neurons (Wang et al., 2009). To explore the functional consequence of mitochondrial redistribution, we were able to demonstrate that overexpression of APP (Wang et al., 2008) or exposure to soluble Aβ oligomers (Wang et al., 2009) led to reduced neuritic mitochondrial density which correlated with reduced spine number and PSD95-positive puncta. More importantly, repopulation of neurites with mitochondria by overexpressing DLP1 in these cell models alleviates synaptic deficits, thus suggesting that abnormal mitochondrial localization is probably the most important contributing factor of synaptic dysfunction in the pathogenesis of AD. Such a notion is strongly supported by evidence presented in this study. Through the use of fly overexpressing Aβ, which demonstrates intracellular accumulation of Aβ in the soma and axon of a small group of neurons, Fu-De Huang’s group identified multiple mitochondrial abnormalities (i.e., depletion of presynaptic and axonal mitochondria, decreased axonal transport of mitochondria, and changes in mitochondrial size and number), along with presynaptic deficits and deficits in motor behavior. Most importantly, the depletion of presynaptic and axonal mitochondria was the earliest detectable phenotype, which placed abnormal mitochondrial distribution likely upstream to Aβ-induced presynaptic deficits and deficits in motor function. Interestingly, Aβ-induced mitochondrial mislocalization is also confirmed in another Aβ-overexpressing fly model (Iijima-Ando et al., 2009). These studies thus provide compelling evidence to support the notion that Aβ-induced abnormal mitochondrial distribution causes synaptic deficits in vivo.

    Early work from Mark Smith and George Perry’s group (Hirai et al., 2001) demonstrated increased ultrastructural damage to mitochondria in susceptible pyramidal neurons in AD brain. They also observed increased size and decreased number of mitochondria in these neurons. These morphometric changes in AD brain were faithfully replicated in Fu-De Huang’s fly model of AD. Given that mitochondrial number and morphology are strictly regulated by the delicate balance of mitochondrial fission/fusion, these findings likely suggest alteration in mitochondrial dynamics. However, without detailed characterization of the changes in mitochondrial fission/fusion machinery, it is probably premature at this stage to suggest impairment in mitochondrial fission in this model because swelling mitochondria were found in cells deficient of mitochondrial fusion (Chen et al., 2007) and during cell death. In fact, neuronal cells expressing APP or exposed to soluble Aβ oligomers demonstrated enhanced mitochondrial fission through differential effects on the expression of mitochondrial fission/fusion proteins and increased phosphorylation, S-nitrosylation, and mitochondrial recruitment of DLP1 (Wang et al., 2009; Cho et al., 2009). Nevertheless, it remains to be determined whether Aβ/APP overexpression leads to mitochondrial fission in vivo. It is of interest to note that Pink1/parkin mutations cause impaired fission in fly models (Poole et al., 2008; Yang et al., 2008; Deng et al., 2008) while enhancing mitochondrial fission in mammalian cells (Dagda et al., 2009; Lutz et al., 2009; Sandebring et al., 2009); therefore, it may still be possible that overexpression of Aβ/APP induces different effects in fly and mouse models.

    It was reported that Aβ fibrils caused acute impairment in axonal transport of mitochondria. More recently, we also reported that soluble Aβ oligomers caused reduced axonal transport of mitochondria in primary hippocampal neurons, similarly affecting both anterograde and retrograde transport. Consistent with these studies, reduced axonal transport of mitochondria is also reported in this current study. Since it occurs later than the presynaptic depletion of mitochondria, the authors suggest that axonal transport deficits may not cause mitochondrial depletion. However, another recent study in a similar Aβ-overexpressing fly model suggests that mitochondrial transport likely contributes to the mislocalization of mitochondria (Iijima-Ando et al., 2009). Therefore, more studies, especially those in mammalian systems, are still needed.

    References:

    . Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci. 2009 Jul 15;29(28):9090-103. PubMed.

    . Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23. PubMed.

    . Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease. PLoS One. 2009;4(12):e8310. PubMed.

    . Mitochondrial abnormalities in Alzheimer's disease. J Neurosci. 2001 May 1;21(9):3017-23. PubMed.

    . Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell. 2007 Aug 10;130(3):548-62. PubMed.

    . S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009 Apr 3;324(5923):102-5. PubMed.

    . The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43. PubMed.

    . Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10793-8. PubMed.

    . The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14503-8. PubMed.

    . Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem. 2009 May 15;284(20):13843-55. Epub 2009 Mar 10 PubMed.

    . Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem. 2009 Aug 21;284(34):22938-51. PubMed.

    . Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. PLoS One. 2009;4(5):e5701. PubMed.

  5. We thank all the commentators on our paper, "Expression of beta amyloid induced age-dependent presynaptic and axonal changes in Drosophila."

    Our examination, through genetic manipulation, of the role of critical mitochondria fission and fusion genes in the mitochondrial abnormalities induced by Aβ expression will be finished soon.

    View all comments by Fu-De Huang

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  1. Abnormal Mitochondrial Dynamics—Early Event in AD, PD?