Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer's disease neurons.
The purpose of our study was to investigate the effects of the mitochondria-targeted antioxidants, MitoQ and SS31, and the anti-aging agent resveratrol on neurons from a mouse model (Tg2576 line) of Alzheimer's disease (AD) and on mouse neuroblastoma (N2a) cells incubated with the amyloid-beta (Abeta) peptide. Using electron and confocal microscopy, gene expression analysis, and biochemical methods, we studied mitochondrial structure and function and neurite outgrowth in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Abeta. In N2a cells only incubated with the Abeta, we found increased expressions of mitochondrial fission genes and decreased expression of fusion genes and also decreased expression of peroxiredoxins. Electron microscopy of the N2a cells incubated with Abeta revealed a significantly increased number of mitochondria, indicating that Abeta fragments mitochondria. Biochemical analysis revealed that function is defective in mitochondria. Neurite outgrowth was significantly decreased in Abeta-incubated N2a cells, indicating that Abeta affects neurite outgrowth. However, in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Abeta, abnormal expression of peroxiredoxins and mitochondrial structural genes were prevented and mitochondrial function was normal; intact mitochondria were present and neurite outgrowth was significantly increased. In primary neurons from amyloid-beta precursor protein transgenic mice that were treated with MitoQ and SS31, neurite outgrowth was significantly increased and cyclophilin D expression was significantly decreased. These findings suggest that MitoQ and SS31 prevent Abeta toxicity, which would warrant the study of MitoQ and SS31 as potential drugs to treat patients with AD.
Manczak
Maria
M
Neurogenetics Laboratory, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
Mao
Peizhong
P
Calkins
Marcus J
MJ
Cornea
Anda
A
Reddy
Arubala P
AP
Murphy
Michael P
MP
Szeto
Hazel H
HH
Park
Byung
B
Reddy
P Hemachandra
PH
D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002461:Cell Line, Transformed / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004347:Drug Interactions; D003576:Electron Transport Complex IV / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010446:Peptide Fragments / Q000633:toxicity*; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; C074636:amyloid beta-protein (25-35); D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; D003576:Electron Transport Complex IV
Ann Neurol. 1991 Oct;30(4):572-80
1789684
J Neurosci Methods. 2008 Feb 15;168(1):134-9
17936365
Adv Physiol Educ. 2006 Dec;30(4):145-51
17108241
J Neurosci. 2001 May 1;21(9):3017-23
11312286
Neuromolecular Med. 2004;5(2):147-62
15075441
JAMA. 2002 Jun 26;287(24):3230-7
12076219
Biochem J. 2004 Oct 1;383(Pt 1):101-9
15233627
Oncogene. 2008 Apr 7;27(16):2320-36
18391974
Cell. 2006 Oct 20;127(2):397-408
17055439
Mol Cell Neurosci. 2007 Jun;35(2):377-82
17490890
Annu Rev Pharmacol Toxicol. 2007;47:629-56
17014364
Curr Protoc Neurosci. 2009 Jul;Chapter 7:Unit 7.17.1-51
19575472
J Neurosci. 2006 Aug 30;26(35):9057-68
16943564
J Biol Chem. 2007 Oct 19;282(42):30523-34
17761673
Am J Pathol. 2008 Aug;173(2):470-82
18599615
Nat Med. 2006 Sep;12(9):1005-15
16960575
Free Radic Biol Med. 2005 Jun 15;38(12):1543-52
15917183
J Am Geriatr Soc. 2008 Feb;56(2):291-5
18047492
Nat Med. 2008 Oct;14(10):1097-105
18806802
Neurology. 2000 Mar 28;54(6):1265-72
10746596
Exp Neurol. 2009 Aug;218(2):286-92
19358844
Nat Rev Neurosci. 2007 Jul;8(7):499-509
17551515
Nat Protoc. 2007;2(6):1490-8
17545985
Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20057-62
19897719
Am J Clin Nutr. 2003 Apr;77(4):975-84
12663300
Trends Mol Med. 2008 Feb;14(2):45-53
18218341
Acta Neuropathol. 2008 Jun;115(6):611-22
18386021
J Immunol Methods. 1983 Dec 16;65(1-2):55-63
6606682
J Neurosci. 2005 Jan 19;25(3):672-9
15659604
Neurodegener Dis. 2008;5(3-4):157-9
18322377
Med Hypotheses. 2004;63(1):8-20
15193340
J Neurosci. 2009 Jul 15;29(28):9090-103
19605646
Hum Mol Genet. 2006 May 1;15(9):1437-49
16551656
Brain Res Rev. 2006 Sep;52(2):316-26
16766037
Am J Physiol Regul Integr Comp Physiol. 2003 Nov;285(5):R1259-67
12855419
Arch Neurol. 2009 Mar;66(3):352-61
19273754
FASEB J. 2005 Dec;19(14):2040-1
16210396
Cell Metab. 2006 Nov;4(5):349-62
17055784
J Bioenerg Biomembr. 2005 Aug;37(4):207-25
16167177
Subcell Biochem. 2007;44:357-74
18084903
Arch Neurol. 2003 Feb;60(2):203-8
12580704
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13576-81
19666610
Physiol Rev. 2001 Apr;81(2):741-66
11274343
Biochem Soc Trans. 2009 Dec;37(Pt 6):1147-60
19909238
Ann Neurol. 1990 May;27(5):457-64
2360787
Nature. 2006 Oct 19;443(7113):787-95
17051205
Genes Dev. 2000 Jan 15;14(2):142-6
10702024
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14670-5
19667196
J Neurosci. 2003 Oct 8;23(27):9046-58
14534238
Science. 1996 Oct 4;274(5284):99-102
8810256
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23
19050078
Cell. 2006 Oct 6;127(1):59-69
17018277
Cell. 2004 Dec 17;119(6):873-87
15607982
J Neurochem. 2002 Jan;80(1):91-100
11796747
J Immunol. 2003 Aug 15;171(4):1623-9
12902457
Science. 2004 Apr 16;304(5669):448-52
15087549
Hum Mol Genet. 2009 Oct 15;18(20):3876-93
19617638
Nat Neurosci. 2008 Apr;11(4):476-87
18344994
J Neurochem. 2006 Jan;96(2):305-13
16219030
Diabetes. 2008 Mar;57(3):563-76
18162510
Ann Pharmacother. 2005 Dec;39(12):2009-14
16227448
J Neurosci Methods. 2004 Jan 15;132(1):101-7
14687679
Arch Neurol. 2004 Jan;61(1):82-8
14732624
Hum Mol Genet. 2004 Jun 15;13(12):1225-40
15115763
Am J Epidemiol. 1998 Jul 1;148(1):38-44
9663402
Antioxid Redox Signal. 2009 Sep;11(9):2095-104
19203217
Ann N Y Acad Sci. 2008 Dec;1147:112-21
19076436