Impaired Balance of Mitochondrial Fission and Fusion in Alzheimer's Disease

Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2009; 29(28):9090-103. DOI: 10.1523/JNEUROSCI.1357-09.2009
Source: PubMed


Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) neurons. In this study, we explored the involvement of an abnormal mitochondrial dynamics by investigating the changes in the expression of mitochondrial fission and fusion proteins in AD brain and the potential cause and consequence of these changes in neuronal cells. We found that mitochondria were redistributed away from axons in the pyramidal neurons of AD brain. Immunoblot analysis revealed that levels of DLP1 (also referred to as Drp1), OPA1, Mfn1, and Mfn2 were significantly reduced whereas levels of Fis1 were significantly increased in AD. Despite their differential effects on mitochondrial morphology, manipulations of these mitochondrial fission and fusion proteins in neuronal cells to mimic their expressional changes in AD caused a similar abnormal mitochondrial distribution pattern, such that mitochondrial density was reduced in the cell periphery of M17 cells or neuronal process of primary neurons and correlated with reduced spine density in the neurite. Interestingly, oligomeric amyloid-beta-derived diffusible ligands (ADDLs) caused mitochondrial fragmentation and reduced mitochondrial density in neuronal processes. More importantly, ADDL-induced synaptic change (i.e., loss of dendritic spine and postsynaptic density protein 95 puncta) correlated with abnormal mitochondrial distribution. DLP1 overexpression, likely through repopulation of neuronal processes with mitochondria, prevented ADDL-induced synaptic loss, suggesting that abnormal mitochondrial dynamics plays an important role in ADDL-induced synaptic abnormalities. Based on these findings, we suggest that an altered balance in mitochondrial fission and fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction in AD brain.

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    • "More importantly, mitochondrial dysfunction occurs early in AD, and several hypotheses regarding Ab mitotoxicity have recently been proposed (Bossy-Wetzel et al., 2004; Canevari et al., 2004; Tillement et al., 2011). The mechanisms that are altered by the bA42 peptide include the following: (1) promotion of the opening of the membrane permeability transition pores (MPT) in isolated brain and liver mitochondria (Moreira et al., 2002), which inhibits respiration and key enzymatic activities (Casley et al., 2002; Tillement et al., 2006); (2) elicitation of an imbalance in mitochondrial fission and fusion that results in mitochondrial fragmentation and an abnormal mitochondrial distribution (Wang et al., 2009; Santos et al., 2010); (3) the bA42 peptide inducing the inhibition of cytochrome c oxidase (also known as respiratory chain complex IV, CcOX, COI or cox) activity in isolated rat and amyloid precursor protein (APP) transgenic mouse brain mitochondria; and (4) copper1-dependent inhibition of human CcOX by dimeric bA in mitochondria from cultured human cells has also been observed (Casley et al., 2002; Herna´ndez-Zimbro´n et al., 2012). Together, these events contribute to mitochondrial and neuronal dysfunction. "
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    ABSTRACT: Oxidative stress is a major risk factor for Alzheimeŕs Disease (AD) that has been suggested to be the trigger of AD pathology. However, whether oxidative damage precedes and contributes directly to the intracellular accumulation of beta amyloid 1-42 (βA42) peptide remains a matter of debate. Chronic exposure to low doses of ozone similar to the levels during a day of high pollution in México City causes a state of oxidative stress that elicits progressive neurodegeneration in the hippocampi of rats. Several reports have demonstrated that the mitochondria are among the first organelles to be affected by oxidative stress and βA42 toxicity and act as sites of the accumulation of βA42, which affects energy metabolism. However, the mechanisms related to the neurodegeneration process and organelle damage that occur in conditions of chronic exposure to low doses of ozone have not been demonstrated. To analyze the effect of chronic ozone chronic exposure on changes in the production and accumulation of the βA42 and βA40 peptides in the mitochondria of hippocampal neurons of rats exposed to ozone, we examined the mitochondrial expression levels of Presenilins 1 and 2and ADAM10 to detect changes related to the oxidative stress caused by low doses of ozone (0.25 ppm). The results revealed significant accumulations of βA42 peptide in the mitochondrial fractions on days 60 and 90 of ozone exposure along with reductions in beta amyloid 1-40 accumulation, significant overexpressions of Pres2 and significant reductions in ADAM 10 expression. Beta amyloid immunodetection revealed that there were some intracellular deposits of beta amyloid 1-42 and that βA42 and the mitochondrial markers OPA1 and COX1 colocalized. These results indicate that the time of exposure to ozone and the accumulation of βA42 in the mitochondria of the hippocampal cells of rats were correlated. Our results suggest that the accumulation of the βA42 peptide may promote mitochondrial dysfunction due to its accumulation and overproduction. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 07/2015; 304. DOI:10.1016/j.neuroscience.2015.07.011 · 3.36 Impact Factor
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    • "Neuronal mitochondrial dysfunction is an early and prominent feature of AD (Wang et al. 2009) as is reduced energy metabolism in the brain (Landau et al. 2011, Shokouhi et al. 2013, Yamane et al. 2013). Diminished neuronal expression of genes encoding subunits of the ETC, as well as decreased expression or activity of many enzymes involved in oxidative metabolism, are also well-documented in AD brains (Cottrell et al. 2001, Gibson et al. 1998, Nagy et al. 1999, Parker et al. 1994). "
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    ABSTRACT: Mitochondrial dysfunction is observed in brains of Alzheimer's Disease patients as well as many rodent model systems including those modeling mutations in preseinilin 1 (PSEN1). The aim of our study was to characterize mitochondrial function and number in fibroblasts from AD patients with PSEN1 mutations. We used biochemical assays, metabolic profiling and fluorescent labeling to assess mitochondrial number and function in fibroblasts from three AD patients compared to fibroblasts from three controls. The mutant AD fibroblasts had increased Aβ42 relative to controls along with reduction in ATP, basal and maximal mitochondrial respiration as well as impaired spare mitochondrial respiratory capacity. Fluorescent staining and expression of genes encoding electron transport chain enzymes showed diminished mitochondrial content in the AD fibroblasts. This study demonstrates that mitochondrial dysfunction is observable in AD fibroblasts and provides evidence that this model system could be useful as a tool to screen disease-modifying compounds.
    Metabolic Brain Disease 04/2015; 30(5). DOI:10.1007/s11011-015-9667-z · 2.64 Impact Factor
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    • "Mounting evidence suggests that Ab causes increased mitochondrial fission and decreased fusion, resulting in mitochondrial fragmentation and neuronal cell death (Wang et al. 2008; Cha et al. 2012). Furthermore, AbOs have also been shown to cause reduced mitochondrial length, suggestive of enhanced mitochondrial fragmentation and cell death, in neurons (Wang et al. 2009; Calkins et al. 2011; Paula-Lima et al. 2011). Mitochondrial fission in mammalian cells is controlled by dynamin-related protein 1 (Drp1) and mitochondrial fission 1 (Fis1), whereas fusion is regulated by mitofusin 1 and 2 (Mfn1/2) and optic atrophy protein 1 (Opa1) (Knott et al. 2008; Cho et al. 2010; Westermann 2010). "
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    ABSTRACT: Mitochondrial dysfunction is implicated in age-related degenerative disorders such as Alzheimer's disease (AD). Maintenance of mitochondrial dynamics is essential for regulating mitochondrial function. Aβ oligomers (AβOs), the typical cause of AD, lead to mitochondrial dysfunction and neuronal loss. AβOs have been shown to induce mitochondrial fragmentation, and their inhibition suppresses mitochondrial dysfunction and neuronal cell death. Oxidative stress is one of the earliest hallmarks of AD. Cyclin-dependent kinase 5 (Cdk5) may cause oxidative stress by disrupting the antioxidant system, including Prx2. Cdk5 is also regarded as a modulator of mitochondrial fission; however, a precise mechanistic link between Cdk5 and mitochondrial dynamics is lacking. We estimated mitochondrial morphology and alterations in mitochondrial morphology-related proteins in N2a cells stably expressing the swedish mutation of amyloid precursor protein (APP), which is known to increase AβO production. We demonstrated that mitochondrial fragmentation by AβOs accompanies reduced Mfn1 and Mfn2 levels. Interestingly, the Cdk5 pathway, including phosphorylation of the Prx2-related oxidative stress, has been shown to regulate Mfn1 and Mfn2 levels. Furthermore, Mfn2, but not Mfn1, overexpression significantly inhibits the AβO-mediated cell death pathway. Therefore, these results indicate that AβO-mediated oxidative stress triggers mitochondrial fragmentation via decreased Mfn2 expression by activating Cdk5-induced Prx2 phosphorylation.
    Journal of Neurochemistry 10/2014; 132(6). DOI:10.1111/jnc.12984 · 4.28 Impact Factor
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