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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    • "Our immunocytochemistry of primary hippocampal neurons revealed fragmented and punctuated immunoreactivity of key mitochondrial enzyme PDHE1α in the neuronal processes of AD neurons, further confirming the presence of mitochondrial fragmentation. It has been previously reported that mitochondrial dynamics are altered in neurons exposed to Aβ37383940. Mitochondrial accumulation of Aβ activates the expression of fission proteins Drp1 and Fis1, meanwhile reducing the expression of fusion proteins such as Mfn1, Mfn2 and Opa1[37,38]. "
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    ABSTRACT: Icariin, a pharmacologically active component isolated from the Chinese herb Epimedium, has been shown to improve spatial learning and memory abilities in Alzheimer's disease (AD) rats through inhibition of Aβ production and tau protein hyperphosphorylation. However, the potential mechanism of icariin-induced protective effects against mitochondrial dysfunctions in AD still remains unclear. In the present study, we investigated the effect of icariin on the modulation of mitochondrial transport and distribution in primary hippocampal cultures from triple-transgenic (3× Tg) AD mice. The results showed that icariin enhanced mitochondrial motility and increased mitochondrial index and mitochondrial length and size in the diseased neurons. Additionally, the expression of the key mitochondrial enzyme, pyruvate dehydrogenase-E1α (PDHE1α), and the post synaptic density protein 95 (PSD95), was preserved in AD neurons after icariin treatment, accompanied by a downregulation of Aβ and phosphorylated tau expression in the corresponding areas. Further study showed that icariin treatment resulted in a decrease in mitochondrial fission protein dynamin-related protein 1 (Drp1) and an increase in fusion protein Mitofusin 2 (Mfn2). These data indicate that icariin can promote mitochondrial transport, protect mitochondria against fragmentation and preserve the expression of mitochondrial and synaptic functional proteins in AD neurons. Thus, icariin may be a potential therapeutic complement for AD and other mitochondrial malfunction-related neuronal degenerative diseases.
    Preview · Article · Jan 2016 · International Journal of Molecular Sciences
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    • "In addition, phosphorylation of Drp1 is increased in the brains of patients with AD [11]. However, the mechanism underlying AβOinduced mitochondrial fragmentation is not understood. "
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    ABSTRACT: Alzheimer's disease (AD), a neurodegenerative disorder, is caused by amyloid-beta oligomers (AβOs). AβOs induce cell death by triggering oxidative stress and mitochondrial dysfunction. A recent study showed that AβO-induced oxidative stress is associated with extracellular signal-regulated kinase (ERK)-dynamin related protein 1 (Drp1)-mediated mitochondrial fission. Reactive oxygen species (ROS) are regulated by antioxidant enzymes, especially peroxiredoxins (Prxs) that scavenge H2O2. These enzymes inhibit neuronal cell death induced by various neurotoxic reagents. However, it is unclear whether Prx5, which is specifically expressed in neuronal cells, protects these cells from AβO-induced damage. In this study, we found that Prx5 expression was upregulated by AβO-induced oxidative stress and that Prx5 decreased ERK-Drp1-mediated mitochondrial fragmentation and apoptosis of HT-22 neuronal cells. Prx5 expression was affected by AβO, and amelioration of oxidative stress by N-acetyl-l-cysteine decreased AβO-induced Prx5 expression. Prx5 overexpression reduced ROS as well as RNS and apoptotic cell death but Prx5 knockdown did not. In addition, Prx5 overexpression ameliorated ERK-Drp1-mediated mitochondrial fragmentation but Prx5 knockdown did not. These results indicated that inducible Prx5 expression by AβO plays a key role in inhibiting both ERK-Drp1-induced mitochondrial fragmentation and neuronal cell death by regulating oxidative stress. Thus, Prx5 may be a new therapeutic agent for treating AD.
    Full-text · Article · Nov 2015 · Free Radical Biology and Medicine
    • "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.
    No preview · Article · Jul 2015 · Neuroscience
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