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Systemic Mitochondrial Dysfunction and the Etiology of Alzheimer's Disease and Down Syndrome Dementia

Issue title: Mitochondria and Neurodegenerative Diseases

Guest editors: Xiongwei Zhu, M. Flint Beal, Xinglong Wang, George Perry and Mark A. Smith

Article type: Research Article

Authors: Coskun, Pinar E.a; b | Wyrembak, Joannea | Derbereva, Olgaa; b | Melkonian, Goara; b | Doran, Ericc | Lott, Ira T.c | Head, Elizabethd; | Cotman, Carl W.d | Wallace, Douglas C.a; b; c; e; *

Affiliations: [a] Mitochondrial and Molecular Medicine and Genetics (MAMMAG), University of California Irvine, Irvine, CA, USA | [b] Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA | [c] Department of Pediatrics, University of California Irvine, Irvine, CA, USA | [d] Institute of Brain Aging, University of California Irvine, Irvine, CA, USA | [e] Department of Ecology and Evolutionary Biology, University of California Irvine, Irvine, CA, USA

Correspondence: [*] Correspondence to: Douglas C. Wallace, Ph.D., Mitochondrial and Molecular Medicine and Genetics (MAMMAG), University of California Irvine, Room number 2010, 2101 Hewitt Hall, Irvine, California 92697, USA. Tel.: +1 949 824 3489; Fax: +1 949 824 6388; E-mail: dwallace@uci.edu.

Note: [1] Current address: Department of Molecular and Biomedical Pharmacology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.

Keywords: Alzheimer's disease, amyloid-β, AβPP, control region, dementia, Down syndrome, mitochondria, mitochondrial dysfunction, mtDNA

DOI: 10.3233/JAD-2010-100351

Journal: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S293-S310, 2010

Accepted 17 April 2010
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Published: 3 June 2010
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Abstract

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-β peptide (Aβ40 and Aβ42) 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 β-secretase activity and mtDNA copy number is inversely correlated with insoluble Aβ40 and Aβ42 levels. Therefore, mtDNA alterations may be responsible for both age-related dementia and the associated neuropathological changes observed in AD and DSAD.

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