Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer's Disease.
Alzheimer's disease (AD) is a chronic neurodegenerative disorder, in which multiple risk factors converge. Despite the complexity of the etiology of the disease, synaptic failure is the pathological basis of cognitive impairment, the cardinal sign of AD. Decreased synaptic density, compromised synaptic transmission, and defected synaptic plasticity are hallmark synaptic pathologies accompanying AD. However, the mechanisms by which synapses are injured in AD-related conditions have not been fully elucidated. Mitochondria are a critical organelle in neurons. The pivotal role of mitochondria in supporting synaptic function and the concomitant occurrence of mitochondrial dysfunction with synaptic stress in postmortem AD brains as well as AD animal models seem to lend the credibility to the hypothesis that mitochondrial defects underlie synaptic failure in AD. This concept is further strengthened by the protective effect of mitochondrial medicine on synaptic function against the toxicity of amyloid-β, a key player in the pathogenesis of AD. In this review, we focus on the association between mitochondrial dysfunction and synaptic transmission deficits in AD. Impaired mitochondrial energy production, deregulated mitochondrial calcium handling, excess mitochondrial reactive oxygen species generation and release play a crucial role in mediating synaptic transmission deregulation in AD. The understanding of the role of mitochondrial dysfunction in synaptic stress may lead to novel therapeutic strategies for the treatment of AD through the protection of synaptic transmission by targeting to mitochondrial deficits.
Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Lan
L
Guo
Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Jing
J
Tian
Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.|Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
Heng
H
Du
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
Alzheimer’s disease; mitochondrial dysfunction; synaptic injury; synaptic mitochondria; synaptic transmission
Acta Neuropathol. 1983;61(2):101-8
6637393
Exp Neurol. 2008 Mar;210(1):7-13
18053990
J Neurochem. 2012 Jan;120 Suppl 1:140-8
22122128
Psychopharmacology (Berl). 2014 Jun;231(11):2361-70
24424781
Neuropharmacology. 1974 Jan;13(1):29-38
4823687
N Engl J Med. 2010 Jan 28;362(4):329-44
20107219
Lancet. 1978 Aug 5;2(8084):318
79110
Biochimie. 2000 Apr;82(4):327-37
10865121
Biochim Biophys Acta. 2011 Dec;1812(12):1630-9
21920438
Ann Neurol. 1991 Oct;30(4):572-80
1789684
J Biomed Eng. 1981 Jul;3(3):183-95
7278203
J Am Geriatr Soc. 1985 Nov;33(11):749-57
2865282
Nat Rev Neurosci. 2012 Dec;13(12):812
23151719
Acta Neurol Scand. 1989 Nov;80(5):461-6
2589014
Int J Geriatr Psychiatry. 1999 Jan;14(1):3-47
10029935
Brain Pathol. 2008 Oct;18(4):484-96
18371174
J Neurochem. 1999 Feb;72(2):700-7
9930743
J Alzheimers Dis. 2009;16(4):763-74
19387111
EMBO J. 1999 Jan 4;18(1):96-108
9878054
Neuroscience. 1992;46(1):1-8
1594095
Neural Plast. 2012;2012:247150
22474602
Lancet. 1979 Oct 20;2(8147):851-2
90944
J Neurophysiol. 1996 Nov;76(5):3325-40
8930276
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13576-81
19666610
Am J Alzheimers Dis Other Demen. 2011 Sep;26(6):450-6
21921084
Q J Nucl Med Mol Imaging. 2014 Dec;58(4):387-97
25366710
J Neurophysiol. 2014 Feb;111(3):648-58
24225540
J Psychopharmacol. 2016 Jan;30(1):3-12
26601905
Clin Neuropharmacol. 1986;9(3):257-63
2872956
Ann N Y Acad Sci. 1987;493:220-33
3035983
Neuron. 2001 Jan;29(1):197-208
11182091
Biochem Soc Trans. 1989 Feb;17(1):69-72
2541034
J Am Geriatr Soc. 1985 Nov;33(11):741-8
2414354
Neurobiol Aging. 1995 May-Jun;16(3):285-98; discussion 298-304
7566338
Biochim Biophys Acta. 2015 Oct;1850(10 ):2041-7
25445707
J Neurol Sci. 1987 Apr;78(2):151-64
3572454
Neuropsychopharmacology. 1998 Dec;19(6):472-80
9803423
J Med Chem. 2000 Nov 2;43(22):4169-79
11063613
J Physiol. 2002 Dec 1;545(Pt 2):521-35
12456831
Dement Geriatr Cogn Disord. 2014;37(1-2):71-85
24107324
Biophys J. 1997 Sep;73(3):1276-80
9284295
J Neurosci. 2011 Apr 13;31(15):5589-95
21490199
Neurobiol Aging. 2003 Dec;24(8):1047-62
14643376
Front Aging Neurosci. 2014 Sep 25;6:252
25309431
Nature. 1977 Jul 28;268(5618):349-51
887166
Hum Mol Genet. 2011 Dec 1;20(23):4515-29
21873260
FASEB J. 1990 Jul;4(10):2745-52
2165009
Ann Neurol. 1992 Nov;32(5):667-76
1449247
PLoS One. 2008 Jul 23;3(7):e2718
18648507
Int Rev Neurobiol. 2002;53:341-85
12512346
Curr Neuropharmacol. 2009 Sep;7(3):160-79
20190959
Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18670-5
20937894
Brain Res. 1983 Nov 28;280(1):119-26
6228286
J Neurol Sci. 1996 Sep 15;141(1-2):39-44
8880690
Neurosci Bull. 2014 Apr;30(2):295-307
24590577
Neurobiol Aging. 2000 May-Jun;21(3):455-62
10858595
Ann N Y Acad Sci. 2000;924:53-61
11193802
Riv Sper Freniatr Med Leg Alien Ment. 1952 Jun;76(2):263-8
12994669
Hum Mol Genet. 2012 Dec 1;21(23):5131-46
22926141
Acta Neurol Scand Suppl. 1996;165:18-24
8740985
Neuron. 2000 Jan;25(1):229-37
10707986
Neurobiol Aging. 2011 Mar;32(3):398-406
19362755
Science. 2009 Apr 3;324(5923):102-5
19342591
J Neurochem. 1983 Nov;41(5):1484-7
6619879
Curr Alzheimer Res. 2012 Jul;9(6):746-58
21875407
Brain Res. 2011 Sep 30;1415:136-48
21872849
Biochim Biophys Acta. 2011 Apr;1812(4):507-13
21241801
Nature. 2006 Oct 19;443(7113):787-95
17051205
Bull Exp Biol Med. 2001 Dec;132(6):1173-6
12152879
Biochim Biophys Acta. 2014 Dec;1842(12 Pt A):2517-27
23507145
Science. 1995 Apr 14;268(5208):239-47
7716515
Neurobiol Aging. 2010 Apr;31(4):614-24
18632189
J Neurol Sci. 2000 Apr 15;175(2):81-90
10831767
Ann Neurol. 2005 May;57(5):695-703
15852400
Neuropsychopharmacology. 2009 Sep;34(10):2323-8
19516251
Prog Neurobiol. 2003 Nov;71(4):269-303
14698765
Curr Pharm Des. 2015;21(34):4960-71
26365140
J Biol Chem. 1964 Sep;239:2910-7
14216443
Trends Neurosci. 2004 Aug;27(8):489-95
15271497
Acta Otolaryngol. 2000 Mar;120(2):247-50
11603783
Pharmaceuticals (Basel). 2012;5(10):1103-19
23226091
Science. 1999 Nov 12;286(5443):1347-50
10558987
J Biol Chem. 2010 Jan 22;285(4):2506-14
19915004
Altern Med Rev. 2008 Jun;13(2):85-115
18590347
J Neurosci. 2011 Jan 12;31(2):630-43
21228172
Drug News Perspect. 2005 Jan-Feb;18(1):13-9
15753972
Brain Res Brain Res Rev. 2000 Apr;32(1):16-28
10751654
J Neurol Neurosurg Psychiatry. 1999 Oct;67(4):558
10610396
FASEB J. 2005 Dec;19(14):2040-1
16210396
J Neurosci. 2010 Jul 7;30(27):9166-71
20610750
Expert Opin Pharmacother. 2014 May;15(7):913-25
24673497
J Mol Biol. 2007 Apr 27;368(2):310-8
17355883
Nat Rev Neurosci. 2012 Mar 07;13(4):240-50
22395804
Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):5887-92
23530243
Science. 2002 Oct 25;298(5594):789-91
12399581
Sci Rep. 2016 Jan 05;6:18725
26729583
Hum Mol Genet. 2006 May 1;15(9):1437-49
16551656
Brain Res. 1985 Mar 11;329(1-2):364-7
3884090
Biochim Biophys Acta. 2010 Jan;1802(1):212-20
19853657
Can J Physiol Pharmacol. 1986 Mar;64(3):341-6
3011232
Mol Neurobiol. 1991;5(2-4):411-9
1823143
Biochem Soc Trans. 2005 Aug;33(Pt 4):563-7
16042545
Radiology. 1997 Jun;203(3):829-36
9169712
J Neurosci. 2000 Oct 15;20(20):7631-9
11027223
Curr Alzheimer Res. 2016;13(8):930-41
26971932
Actual Pharmacol (Paris). 1974;27:45-67
4157158
Front Synaptic Neurosci. 2010 Sep 22;2:139
21423525
Neuron. 2009 Jun 25;62(6):788-801
19555648
Expert Rev Pharmacoecon Outcomes Res. 2015;15(4):565-78
26176750
Neurology. 1995 Mar;45(3 Pt 1):482-6
7898701
J Neurosci. 2009 Jul 15;29(28):9090-103
19605646
J Neurochem. 1974 Oct;23(4):865-7
4430925
Neuropharmacology. 2011 Feb-Mar;60(2-3):223-34
20850464
J Neurol Neurosurg Psychiatry. 1999 Feb;66(2):137-47
10071091
J Neural Transm (Vienna). 1998;105(2-3):269-77
9660105
Neuropharmacology. 2015 Sep;96(Pt B):255-62
25514383
J Biomed Eng. 1982 Jul;4(3):206-12
6289009
Synapse. 2005 Oct;58(1):45-52
16037952
Neurosci Res. 2011 May;70(1):9-15
21352858
Science. 2004 Apr 16;304(5669):448-52
15087549
CNS Drugs. 2001;15(2):85-91
11460892
Biochim Biophys Acta. 2014 Aug;1842(8):1167
24686117
Neurology. 1994 Jun;44(6):1090-6
8208407
J Cell Biol. 2003 Nov 10;163(3):441-3
14610050
Biosci Rep. 2001 Dec;21(6):789-800
12166828
PLoS One. 2013;8(1):e54914
23382999
Drug Discov Today. 2013 Dec;18(23-24):1185-99
24051397
PLoS One. 2013 Nov 28;8(11):e81244
24312282
FASEB J. 2009 Aug;23(8):2459-66
19346295
J Biol Chem. 1996 Nov 1;271(44):27229-32
8910293
J Neurosci. 2010 Apr 28;30(17 ):5948-57
20427654
Mitochondrion. 2006 Dec;6(6):323-30
17123871
Mol Cell Endocrinol. 2013 Oct 15;379(1-2):62-73
23628605
Biochim Biophys Acta. 1968 Oct 22;164(2):448-50
4388821
Front Cell Neurosci. 2014 Feb 10;8:34
24574970
Physiol Behav. 2002 Dec;77(4-5):601-5
12527006
Brain Res. 1994 Sep 19;657(1-2):294-9
7820630
Ann Neurol. 1995 Mar;37(3):300-12
7695230
J Neurol Neurosurg Psychiatry. 1985 May;48(5):469-71
2860210
Neurobiol Aging. 1995 May-Jun;16(3):381-7
7566347
Hum Mol Genet. 2011 Jul 1;20(13):2495-509
21459773
Lancet. 2006 Jul 29;368(9533):387-403
16876668
Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10580-5
24979777
PLoS One. 2015 Dec 03;10(12):e0144068
26632816
Neurosci Lett. 1994 Aug 15;177(1-2):139-42
7824166
J Neurosci Res. 2002 Jul 15;69(2):257-67
12111807
J Nutr Sci Vitaminol (Tokyo). 2006 Aug;52(4):248-55
17087050
Front Endocrinol (Lausanne). 2013 Oct 15;4:149
24133485
J Neuropathol Exp Neurol. 1997 Aug;56(8):933-44
9258263
Basic Clin Pharmacol Toxicol. 2016 Aug;119(2):149-60
27001133
Acta Neuropathol. 1994;87(2):135-42
8171963
Hum Mol Genet. 2012 Jun 1;21(11):2538-47
22367970
N Engl J Med. 1979 Aug 9;301(6):330
377082
Mol Neurobiol. 2016 Jan;53(1):648-661
25511446
Biochim Biophys Acta. 1970 Feb 10;202(1):35-42
4392038
J Alzheimers Dis. 2010;20 Suppl 2:S499-512
20413847
Nutrition. 2011 Jan;27(1):3-20
21035308
J Mol Biol. 2007 Aug 3;371(1):222-34
17570395
Autophagy. 2007 Nov-Dec;3(6):614-5
17786024
J Cereb Blood Flow Metab. 2001 Oct;21(10):1133-45
11598490
Brain Res Brain Res Rev. 2005 Nov;49(3):618-32
16269322
Biochem Biophys Res Commun. 1994 Apr 15;200(1):187-94
8166686
Psychiatr Danub. 2015 Mar;27(1):14-24
25751428
IUBMB Life. 2008 Sep;60(9):609-19
18543277
Cell Mol Life Sci. 2003 May;60(5):942-60
12827282
J Physiol. 2003 Apr 15;548(Pt 2):425-38
12588898
Biochim Biophys Acta. 2014 Aug;1842(8):1219-31
24071439
J Neurochem. 1994 Dec;63(6):2179-84
7964738
Neurology. 2001 Aug 28;57(4):671-5
11524477
Neurobiol Aging. 2007 Sep;28(9):1330-9
16860440
Cold Spring Harb Perspect Biol. 2012 May 01;4(5):null
22491782
J Physiol. 2000 Nov 15;529 Pt 1:37-47
11080249
Curr Opin Neurobiol. 1999 Jun;9(3):305-13
10395573
J Neurochem. 2005 Jul;94(2):299-306
15998281
J Neurochem. 1995 May;64(5):2312-8
7722517
Ann N Y Acad Sci. 1999;893:154-75
10672236
Annu Rev Neurosci. 2004;27:509-47
15217342
Cell. 2005 Sep 9;122(5):669-82
16125763
Trends Mol Med. 2008 Feb;14(2):45-53
18218341
J Neural Transm (Vienna). 1998;105(8-9):855-70
9869323
Behav Brain Res. 2011 Aug 10;221(2):555-63
21145918
Brain Res. 1995 Sep 11;691(1-2):169-79
8590049
J Neurosci. 2002 Dec 15;22(24):10653-61
12486158
Neurosci Lett. 1989 Aug 28;103(2):234-9
2505201
Nat Med. 2008 Oct;14(10):1097-105
18806802
Neuron. 2005 Aug 4;47(3):331-3
16055057
Nature. 2005 Mar 31;434(7033):658-62
15800627
Brain Res. 2005 Jan 7;1031(1):101-8
15621017
Mol Brain. 2015 Nov 24;8(1):78
26603284
Ann N Y Acad Sci. 2003 Nov;1003:391-4
14684469
PLoS One. 2016 Mar 04;11(3):e0150441
26942905
Antioxid Redox Signal. 2012 Jun 15;16(12):1467-75
21942330
Am J Pathol. 1991 Jan;138(1):235-46
1899001
Mol Neurodegener. 2011 Aug 26;6(1):63
21871088
Am J Psychiatry. 2005 Apr;162(4):676-82
15800138
Prog Neurobiol. 1980;14(2-3):99-119
6999538
Neurosci Lett. 1995 Dec 29;202(1-2):25-8
8787822
Adv Anat Embryol Cell Biol. 2015;215:1-162
25920101
Lancet. 1977 Oct 15;2(8042):826-7
71636
Neuromolecular Med. 2008;10(4):291-315
18566920
J Physiol. 1970 Jan;206(1):145-66
5498453
Neuroscience. 2009 Mar 3;159(1):308-15
18721865
Neuron. 2003 Jul 31;39(3):409-21
12895417
J Alzheimers Dis. 2013;34(4):887-96
23313923
Neurobiol Aging. 1992 May-Jun;13(3):405-11
1625770
J Biol Chem. 2009 Apr 3;284(14):9011-5
19028688
CNS Drugs. 2003;17(9):641-52
12828500
J Cell Sci. 2006 Dec 1;119(Pt 23):4926-34
17105774
J Neurosci Res. 2001 Dec 1;66(5):763-70
11746400
Neurodegener Dis. 2010;7(4):251-9
20551690
Neurochem Int. 2009 Jul-Aug;55(1-3):9-12
19428801
Nat Commun. 2016 May 06;7:11483
27151236
Behav Brain Res. 2008 Sep 1;192(1):106-13
18359102
J Alzheimers Dis. 2007 Mar;11(1):97-116
17361039
Biochim Biophys Acta. 2012 May;1822(5):639-49
22037588
Neural Plast. 2016;2016:3985063
26885402
FEBS Lett. 2010 May 17;584(10):1942-7
20074570
Biochem Biophys Res Commun. 1976 Sep 7;72(1):24-32
985471
Int J Biochem Cell Biol. 2010 May;42(5):560-72
20067840
J Neurophysiol. 1997 Jul;78(1):281-94
9242280
J Neurophysiol. 2012 Dec;108(11):3059-67
22972962
J Neural Transm Suppl. 2001;(61):263-72
11771749
Adv Exp Med Biol. 2012;942:269-86
22399427
J Alzheimers Dis. 2011;24(4):759-66
21321399
CNS Spectr. 2009 Aug;14(8 Suppl 7):8-13; discussion 16-8
19890241
Arch Biochem Biophys. 2011 Apr 1;508(1):1-12
21176768
Biochim Biophys Acta. 2009 Nov;1787(11):1291-308
19161975
Neurology. 2001 Jan 9;56(1):127-9
11148253
J Neurosci. 2001 May 1;21(9):3017-23
11312286
Drug News Perspect. 1998 Nov;11(9):523-69
15616669
J Neurosci. 1992 Feb;12(2):376-89
1346802
J Alzheimers Dis. 2010;20 Suppl 2:S609-31
20463406
J Neurosci. 2002 Mar 1;22(5):1648-67
11880495
J Neurosci. 2002 Jul 15;22(14):5840-7
12122046