Systemic mitochondrial dysfunction and the etiology of Alzheimer's disease and down syndrome dementia.
Increasing evidence is implicating mitochondrial dysfunction as a central factor in the etiology of Alzheimer's disease (AD). The most significant risk factor in AD is advanced age and an important neuropathological correlate of AD is the deposition of amyloid-beta peptide (Abeta40 and Abeta42) in the brain. An AD-like dementia is also common in older individuals with Down syndrome (DS), though with a much earlier onset. We have shown that somatic mitochondrial DNA (mtDNA) control region (CR) mutations accumulate with age in post-mitotic tissues including the brain and that the level of mtDNA mutations is markedly elevated in the brains of AD patients. The elevated mtDNA CR mutations in AD brains are associated with a reduction in the mtDNA copy number and in the mtDNA L-strand transcript levels. We now show that mtDNA CR mutations increase with age in control brains; that they are markedly elevated in the brains of AD and DS and dementia (DSAD) patients; and that the increased mtDNA CR mutation rate in DSAD brains is associated with reduced mtDNA copy number and L-strand transcripts. The increased mtDNA CR mutation rate is also seen in peripheral blood DNA and in lymphoblastoid cell DNAs of AD and DSAD patients, and distinctive somatic mtDNA mutations, often at high heteroplasmy levels, are seen in AD and DSAD brain and blood cells DNA. In aging, DS, and DSAD, the mtDNA mutation level is positively correlated with beta-secretase activity and mtDNA copy number is inversely correlated with insoluble Abeta40 and Abeta42 levels. Therefore, mtDNA alterations may be responsible for both age-related dementia and the associated neuropathological changes observed in AD and DSAD.
Coskun
Pinar E
PE
Mitochondrial and Molecular Medicine and Genetics, University of California Irvine, Irvine, CA, USA.
Wyrembak
Joanne
J
Derbereva
Olga
O
Melkonian
Goar
G
Doran
Eric
E
Lott
Ira T
IT
Head
Elizabeth
E
Cotman
Carl W
CW
Wallace
Douglas C
DC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics; D003704:Dementia / Q000150:complications / Q000209:etiology*; D004314:Down Syndrome / Q000150:complications / Q000209:etiology*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D055815:Young Adult
D016229:Amyloid beta-Peptides; D004272:DNA, Mitochondrial; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
Int J Exp Pathol. 2005 Jun;86(3):161-71
15910550
J Neurochem. 1994 Dec;63(6):2179-84
7964738
Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20057-62
19897719
Neurosci Lett. 2004 Jul 15;365(1):28-32
15234467
Genomics. 1993 Jul;17(1):171-84
8104867
Chang Gung Med J. 2009 Mar-Apr;32(2):113-32
19403001
J Biol Chem. 2006 Aug 25;281(34):24647-52
16790426
Science. 1999 Oct 22;286(5440):774-9
10531063
Brain Res Mol Brain Res. 1999 Jul 23;71(1):69-77
10407188
Cell Mol Life Sci. 2000 Nov;57(12):1810-6
11130185
Biochim Biophys Acta. 2000 Apr 17;1496(2-3):341-55
10771102
Nature. 1995 Jun 29;375(6534):734-5
7596402
Mol Cells. 2003 Apr 30;15(2):181-5
12803480
Ann N Y Acad Sci. 1999;893:176-91
10672237
Nature. 1991 Oct 31;353(6347):844-6
1944558
Science. 1991 Oct 4;254(5028):97-9
1925564
Antioxid Redox Signal. 2005 Sep-Oct;7(9-10):1101-9
16115014
Am J Med Genet. 1999 Jul 2;85(1):20-30
10377009
Life Sci. 2001 May 4;68(24):2741-50
11400916
Hum Mutat. 2000 Jan;15(1):120-1
10612844
Nature. 1991 Feb 21;349(6311):704-6
1671712
Methods Mol Biol. 2002;208:145-64
12229286
Brain Res Brain Res Rev. 2005 Nov;49(3):618-32
16269322
Annu Rev Neurosci. 1994;17:489-517
8210185
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10726-31
15247418
Nature. 1995 Dec 21-28;378(6559):776-9
8524410
Annu Rev Genet. 2005;39:359-407
16285865
Proc Natl Acad Sci U S A. 1985 Jan;82(2):351-5
2982153
Science. 1993 Aug 13;261(5123):921-3
8346443
Neurobiol Aging. 2005 Mar;26(3):383-9
15639317
Neurology. 1990 Aug;40(8):1302-3
2166249
Pediatr Res. 1987 Jan;21(1):88-92
2948148
Neurobiol Aging. 2007 Oct;28(10):1493-506
16904243
Nat Med. 1996 Jan;2(1):93-5
8564851
Ann N Y Acad Sci. 2008 Dec;1147:221-32
19076444
J Dev Behav Pediatr. 2001 Feb;22(1):40-59
11265922
Hum Genet. 2001 Mar;108(3):194-8
11354629
Nucleic Acids Res. 2000 Nov 1;28(21):4350-5
11058135
Biochem Biophys Res Commun. 1997 Dec 18;241(2):221-5
9425253
FASEB J. 2005 Dec;19(14):2040-1
16210396
Neurology. 2000 Jul 25;55(2):302-4
10908912
Curr Genet. 1987;12(2):81-90
2896550
Biochem Biophys Res Commun. 2002 Dec 6;299(3):373-6
12445809
Alzheimer Dis Assoc Disord. 1987;1(1):3-8
3331112
J Neurosci. 1997 Jun 15;17(12):4612-22
9169522
Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6892-5
7624338
Brain Dev. 2003 Apr;25(3):180-5
12689696
Science. 1992 Nov 6;258(5084):995-8
1359644
Ophthalmic Paediatr Genet. 1989 Dec;10(4):271-7
2534164
Biochem Biophys Res Commun. 2005 Mar 4;328(1):1-5
15670741
Am J Nurs. 2006 Dec;106(12):40-7; quiz 47-8
17133003
Eur J Med Res. 1997 Mar 24;2(3):111-3
9113500
Prog Neuropsychopharmacol Biol Psychiatry. 2005 Mar;29(3):407-10
15795049
Brain Res. 1984 Sep;318(1):37-44
6237715
FEBS Lett. 1999 Aug 20;457(1):131-4
10486579
Acta Neuropathol. 1999 Apr;97(4):346-54
10208273
Neuropathol Appl Neurobiol. 1997 Aug;23(4):315-21
9292870
Annu Rev Biochem. 2007;76:781-821
17506638
Free Radic Biol Med. 2008 Nov 15;45(10):1420-5
18762245
Trends Genet. 2000 Nov;16(11):500-5
11074292
Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18694-9
16344479
Free Radic Biol Med. 1998 Dec;25(9):1044-8
9870557
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14670-5
19667196
Ment Retard Dev Disabil Res Rev. 2001;7(3):172-8
11553933
Neurology. 1996 Jul;47(1):254-6
8710088
Biochim Biophys Acta. 2009 May;1787(5):296-302
19366608
J Alzheimers Dis. 2002 Dec;4(6):479-86
12515899
Ann Neurol. 2005 May;57(5):695-703
15852400
Am J Pathol. 2004 Feb;164(2):719-25
14742275
Neurobiol Aging. 2000 May-Jun;21(3):455-62
10858595
Science. 2004 Apr 16;304(5669):448-52
15087549
N Engl J Med. 1989 Jun 1;320(22):1446-52
2566117
J Neurochem. 1992 Aug;59(2):776-9
1321237
Neurology. 1994 Jun;44(6):1090-6
8208407
Lancet. 1989 Mar 25;1(8639):642-5
2564461
J Neurochem. 2005 Feb;92(3):494-504
15659220
Proteomics. 2002 Nov;2(11):1539-46
12442254
Pharmacogenomics J. 2010 Oct;10(5):375-84
20029386
Am J Hum Genet. 1991 Jun;48(6):1034-50
2035524
FASEB J. 2005 Apr;19(6):597-8
15665036
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4022-7
11274426
Genomics. 1994 Sep 15;23(2):471-6
7835898
Curr Opin Neurol. 2004 Apr;17(2):95-100
15021233
PLoS One. 2009 Aug 07;4(8):e6501
19668339
Proc Natl Acad Sci U S A. 1987 Nov;84(21):7580-4
2823266
Vasc Health Risk Manag. 2008;4(3):721-30
18827923
Mitochondrion. 2005 Apr;5(2):109-19
16050977
Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5949-54
20231448
Neurology. 1993 Jul;43(7):1377-84
8327141
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5644-51
16567625
Am J Med Genet C Semin Med Genet. 2006 Aug 15;142C(3):196-205
17048356
Nature. 1995 Jun 29;375(6534):754-60
7596406
Neurobiol Aging. 1998 Jan-Feb;19(1 Suppl):S47-51
9562468
J Neurosci Res. 2002 Nov 1;70(3):357-60
12391597