Mitochondrial Complex I Inhibition Accelerates Amyloid Toxicity
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Alzheimer's disease (AD) is neurodegenerative disease, characterized by the progressive decline of memory, cognitive functions, and changes in personality. The major pathological features in postmortem brains are neurofibrillary tangles and amyloid beta (Aβ) deposits. The majority of AD cases are sporadic and age-related. Although AD pathogene-sis has not been established, aging and declining mitochondrial function has been associated. Mitochondrial dysfunction has been observed in AD patients' brains and AD mice models, and the mice with a genetic defect in mitochondrial com-plex I showed enhanced Aβ level in vivo. To elucidate the role of mitochondrial complex I in AD, we used SH-SY5Y cells transfected with DNA constructs expressing human amyloid precursor protein (APP) or human Swedish APP mutant (APP-swe). The expression of APP-swe increased the level of Aβ protein in comparison with control. When complex I was inhibited by rotenone, the increase of ROS level was remarkably higher in the cells overexpressing APP-swe com-pared to control. The number of dead cell was significantly increased in APP-swe-expressing cells by complex I inhibition. We suggest that complex I dysfunction accelerate amyloid toxicity and mitochondrial complex I dysfunction in aging may contribute to the pathogenesis of sporadic AD
Abstract
Alzheimer's disease (AD) is neurodegenerative disease, characterized by the progressive decline of memory, cognitive functions, and changes in personality. The major pathological features in postmortem brains are neurofibrillary tangles and amyloid beta (Aβ) deposits. The majority of AD cases are sporadic and age-related. Although AD pathogene-sis has not been established, aging and declining mitochondrial function has been associated. Mitochondrial dysfunction has been observed in AD patients' brains and AD mice models, and the mice with a genetic defect in mitochondrial com-plex I showed enhanced Aβ level in vivo. To elucidate the role of mitochondrial complex I in AD, we used SH-SY5Y cells transfected with DNA constructs expressing human amyloid precursor protein (APP) or human Swedish APP mutant (APP-swe). The expression of APP-swe increased the level of Aβ protein in comparison with control. When complex I was inhibited by rotenone, the increase of ROS level was remarkably higher in the cells overexpressing APP-swe com-pared to control. The number of dead cell was significantly increased in APP-swe-expressing cells by complex I inhibition. We suggest that complex I dysfunction accelerate amyloid toxicity and mitochondrial complex I dysfunction in aging may contribute to the pathogenesis of sporadic AD
참고문헌 (31)
- Choi WS, "Phos-phorylation of p38 MAPK induced by oxidative stress is linked to activation of both caspase-8- and -9-me-diated apoptotic pathways in dopaminergic neurons", J Biol Chem, 279(19), pp.20451~20460 (2004)
- Choi WS, "Two distinct mechanisms are involved in 6-hyd-roxydopamine- and MPP+-induced dopaminergic neu-ronal cell death: role of caspases, ROS, and JNK", J Neurosci Res, 57, pp.86~94 (1999)
- Devi L, "Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction", J Neurosci, 26, pp.9057~9068 (2006)
- Eckert A, "Mitochondrial dysfunction, apoptotic cell death, and Alzheimer’s disease", Biochem Pharmacol, 66, pp.1627~1634 (2003)
- Fernandez-Vizarra P, "Intra- and extracellular Abeta and PHF in clinically evaluated cases of Alzheimer’'s disease", Histol Histopathol, 19, pp.823~844 (2004)
- Gandy S, "The role of cerebral amyloid β accumula-tion in common forms of Alzheimer disease", J Clin In-vest, 115, pp.1121~1129 (2005)
- Gibson GE, "Oxidative processes in the brain and non-neuronal tissues as biomarkers of Alz-heimer’'s disease", Front Biosci, 7, pp.d1007~d1015 (2002)
- Haass C, "Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amy-loid betapeptide", Nat Rev Mol Cell Biol, 8, pp.101~112 (2007)
- + oxidation-reduc-tion state, "Biochem J", 2002, 545~553
- Lecoeur H, "Nuclear apoptosis detection by flow cytometry: Influence of endogenous endonucleases", Exp. Cell Res, 277, pp.1~14 (2002)
- Leuner K, "Mito-chondrial dysfunction: The first domino in brain aging and Alzheimer's disease?", Antioxid Redox Signal, 9, pp.1659~1675 (2007)
- Leuner K, "Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation", Antioxid Redox Signal, 16, pp.1421~1433 (2012)
- Lustbader JW, "ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease", Science, 304, pp.448~452 (2004)
- Manczak M, "Time-course of mitochondrial gene expressions in mice brains: implications for mitochondrial dysfunction, oxi-dative damage, and cytochrome c in aging", J Neuro-chem, 92, pp.494~504 (2005)
- Mattson MP, "Energetics and oxidative stress in synaptic plasticity and neurodegenerative disorders", Neuromolecular Med, 2, pp.215~231 (2002)
- Mattson MP, "Mitochondrial regulation of neuronal plasticity", Neurochem Res, 32, pp.707~715 (2007)
- Mattson MP, "Mitochon-dria in neuroplasticity and neurological disorders", Neu-ron, 60, pp.748~766 (2008)
- Maurer I, "A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients", Neurobiol Aging, 21, pp.455~462 (2002)
- Paradies G, "Oxidative stress, mitochondrial bioenergetics, and car-diolipin in aging", Free Radic Biol Med, 48, pp.1286~1295 (2010)
- Parker WD Jr, "Cytochrome oxidase deficiency in Alzheimer's disease", Neurology, 40, pp.1302~1303 (1990)
- Pavlov PF, "Mitochondrial accumulation of APP and Abeta: significance for Alzheimer disease pathogenesis", J Cell Mol Med, 13, pp.4137~4145 (2009)
- Petrosillo G, "Mitochondrial dysfunction in rat brain with aging Involvement of complex I, reactive oxygen species and cardiolipin", Neurochem Int, 53, pp.126~131 (2008)
- Querfurth HW, "Alzheimer’'s disease", N Engl J Med, 362, pp.329~344 (2010)
- Reddy PH, "Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cog-nitive decline in aging and Alzheimer's disease", Trends Mol Med, 4, pp.45~53 (2008)
- Reddy PH, "The role of mitochondria in neuro-degenerative diseases: mitochondria as a therapeutic tar-get in Alzheimer’s disease", CNS Spectr, 14, pp.8~18 (2009)
- Reddy PH, "Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease", Exp Neurol, 218, pp.286~292 (2009)
- Rhein V, "Effects of Alzheimer’'s amyloid-beta and tau protein on mitochondrial function-role of glucose metabolism and insulin signalling", Arch Phy-siol Biochem, 113, pp.131~141 (2007)
- Selkoe DJ, "Translating cell biology into therapeutic advances in Alzheimer's disease", Nature, 399, pp.A23~A31 (1999)
- Smith MA, "Oxidative damage in Alz-heimer's", Nature, 382, pp.120~121 (1996)
- Varadarajan S, "Review: Alzheimer's amyloid β-peptide-associated free radical oxidative stress and neurotoxicity", J Struct Biol, 130, pp.184~208 (2000)
- Zhang YW, "APP pro-cessing in Alzheimer's disease", Mol Brain, 4, pp.3~ (2011)