. Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10726-31. PubMed.

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  1. Etiology of late-onset Alzheimer’s disease (AD) is unknown; the paper of Coskun et al. [1] lends further support to an exciting hypothesis that it may be caused by somatic mutations in mtDNA. Mitochondria have long been known as a major source of reactive oxygen species (ROS) in actively metabolic cells; AD appears to most strongly affect brain regions with the highest metabolic rate and highest expression of mitochondrial enzymes. Thus, defects in mitochondrial oxidative phosphorylation and increased generation of ROS by defective mitochondria might mediate the relationship between late-onset AD and mtDNA mutations.

    At a first glance, this mechanism is only relevant to the development of late-onset AD and seems to be unrelated to early-onset forms of the disease which are caused by point mutations in APP and presenilins; such mutations result in accelerated production of amyloid-β (Aβ). Thus, the question of major importance remains, how can we combine late-onset and early-onset AD within such mitochondrial hypothesis? Increased production of Aβ is a probable answer.

    Several years ago, we showed that at low-nanomolar concentrations (i.e., those circulating in CSF and plasma), Aβ is monomeric and functions as an antioxidant [2, 3]. Mechanistically, the antioxidative activity of Aβ is related to its strong capacity to bind transition metal ions [4]; Aβ may therefore function as a metal-chelating, preventive antioxidant under normal physiologic conditions. This conclusion is consistent with results of other studies demonstrating that at low-nanomolar concentrations, Aβ has beneficial effects on neuron survival, axonal length, and neurite outgrowth (see [5, 6] for review).

    Various stress conditions are known to increase Aβ production. Importantly, generation of Aβ increases under oxidative stress induced by different mechanisms (H2O2, UV irradiation, etc.) [5, 6]. Available data strongly suggest that Aβ behaves as a positive acute-phase reactant; antioxidant metal-chelating properties of Aβ may provide a rationale for this phenomenon. Indeed, an increase in Aβ production may be aimed at chelating potentially harmful transition metal ions which can be released, e.g., from metal-binding proteins, during abnormal cellular metabolism and otherwise catalyze adverse oxidation of biomolecules. This mechanism implies that transition metal ions become abnormally sequestrated and need to be chelated in a redox-inactive form by Aβ; indeed, metabolism of transition metals is heavily impaired in AD brains [7]. Oxidative damage to neurons is one of the earliest pathological events in AD [8]; accelerated lipid peroxidation precedes accumulation of Aβ in AD transgenic mice [9]. These data suggest that increased ROS production by defective mitochondria in AD brains may lead to increased generation of Aβ as a compensatory protective response.

    Historically, Aβ has been long considered as a key pro-oxidant in AD [10]. However, to accelerate oxidation, Aβ must be present in concentrations greatly exceeding those normally measured in biological fluids (i.e., micromolar vs. nanomolar; see [2, 5]). In addition, Aβ must be aggregated to fibrils by transition metals; fibrillated Aβ is highly toxic for neurons and other cells [11]. We have therefore hypothesized that Aβ may become a pro-oxidant from an antioxidant, if its concentration increases enough to induce its substantial aggregation and if transition metal ions are available to catalyze this process [5]. This is exactly what Coskun et al. propose in their excellent paper [1]; unfortunately, it does not contain a reference to our work. Furthermore, we have postulated that increased production of Aβ as a result of elevated production of ROS by defective mitochondria with subsequent chelation of transition metal ions, accumulation of toxic Aβ-metal complexes, production of ROS, and neurotoxicity form the temporal sequence of events in the development of late-onset AD [5].

    According to this view, development of AD equally occurs along the pathway of increased Aβ production in early-onset forms of the disease; the major difference between the early- and late-onset forms lies in the elevated rate of Aβ production in early-onset AD due to the presence of genetic defects in APP and presenilins, which should accelerate formation of toxic Aβ-metal complexes and the development of the disease. Targeting a pathologically increased formation of such complexes (i.e. by metal chelators [12]) therefore remains a promising therapeutic strategy in both early- and late-onset AD; since Aβ appears to represent an important protective molecule, great caution must be however exercised about this approach, which may not target monomeric Aβ (cf. studies of AD vaccine).

    References:
    1. P.E. Coskun, M.F. Beal and D.C. Wallace. Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10726-31. Epub 2004 Jul 09. Abstract

    2. A. Kontush, C. Berndt, W. Weber, V. Akopyan, S. Arlt, S. Schippling and U. Beisiegel. Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic Biol Med. 2001 Jan 1;30(1):119-28. Abstract

    3. A. Kontush and C.S. Atwood. Amyloid-beta: phylogenesis of a chameleon.
    Brain Res Brain Res Rev. 2004 Aug;46(1):118-20. No abstract available. Abstract

    4. C.S. Atwood, R.C. Scarpa, X. Huang, R.D. Moir, W.D. Jones, D.P. Fairlie, R.E. Tanzi and A.I. Bush. Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42. J Neurochem. 2000 Sep;75(3):1219-33. Abstract

    5. A. Kontush. Amyloid-beta: an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer's disease. Free Radic Biol Med. 2001 Nov 1;31(9):1120-31. Review. Abstract

    6. C.S. Atwood, M.E. Obrenovich, T. Liu, H. Chan, G. Perry, M.A. Smith and R.N. Martins. Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res Brain Res Rev. 2003 Sep;43(1):1-16. Review. Abstract

    7. A.I. Bush. The metallobiology of Alzheimer's disease. Trends Neurosci. 2003 Apr;26(4):207-14. Review. Abstract

    8. M.A. Smith, C.A. Rottkamp, A. Nunomura, A.K. Raina and G. Perry. Oxidative stress in Alzheimer's disease. Biochim Biophys Acta. 2000 Jul 26;1502(1):139-44. Review. Abstract

    9. D. Pratico, K. Uryu, S. Leight, J.Q. Trojanoswki and V.M. Lee. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci. 2001 Jun 15;21(12):4183-7. Abstract

    10. W.R. Markesbery. Oxidative stress hypothesis in Alzheimer's disease.
    Free Radic Biol Med. 1997;23(1):134-47. Review. Abstract

    11. L.L. Iversen, R.J. Mortishire-Smith, S.J. Pollack and M.S. Shearman. The toxicity in vitro of beta-amyloid protein. Biochem J. 1995 Oct 1;311 ( Pt 1):1-16. Review. No abstract available. Abstract

    12. C.W. Ritchie, A.I. Bush, A. Mackinnon, S. Macfarlane, M. Mastwyk, L. MacGregor, L. Kiers, R. Cherny, Q.X. Li, A. Tammer, D. Carrington, C. Mavros, I. Volitakis, M. Xilinas, D. Ames, S. Davis, K. Beyreuther, R.E. Tanzi and C.L. Masters. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial.
    Arch Neurol. 2003 Dec;60(12):1685-91. Erratum in: Arch Neurol. 2004 May;61(5):776. Abstract

  2. Mitochondria and Alzheimer’s Disease: A Complex Interrelationship

    Recently, Coskun and colleagues (2004) reported that brains from patients with Alzheimer's disease (AD) present somatic mtDNA control-region mutations, especially in individuals older than 80 years, which supports the mitochondrial hypothesis for AD pathophysiology. However, the doubt remains whether these somatic mtDNA mutations are the cause or consequence of AD pathophysiology. If somatic mutations of mtDNA are a cause of AD, these mutations should appear in the vulnerable brain regions affected by the disease. However, this same pattern will be also observed if the somatic mutation of mtDNA is a consequence of AD pathophysiology. So, how and when do the somatic mutations of mtDNA accumulate in specific regions of brain?

    A recent study suggests that DNA damage, recognized by the formation of 8-hydroxyguanosine (8OHG), a marker of nucleic acid oxidation, is markedly increased in the promoters of genes whose expression is decreased in the aged human cortex (Lu et al., 2004). Since modifications of nucleic acid bases cause mutations, this study also suggests that oxidative stress can cause mutations in gene promoters even in aged control brains.

    Coskun et al. (2004) also observed that the number of mtDNA is decreased in brains of AD patients. It is known that the nucleus regulates the replication of mitochondria according to the metabolic needs of the cell. When cells possess a large amount of mitochondria harboring damaged mtDNA, they cannot function properly to maintain normal energetic metabolism. In that case, dysfunctional mitochondria are responsible for an increased leakage of free electrons that causes the production of harmful reactive oxygen species (ROS). In such situations, the suppression of the replication of abnormal mitochondria seems to be effective against excess ROS production.

    A previous study from our laboratory showed the opposite results with mtDNA (Hirai et al., 2001). Using in-situ hybridization, we observed that brains from AD patients present a striking increase in mtDNA. When we analyzed mtDNA changes by PCR, we found only small differences between AD and age-matched controls, even in cases where the in-situ hybridization technique showed a fourfold mtDNA increase. Judging from our observations that damaged mtDNA is restricted to neurons vulnerable in AD, we should be cautious in the interpretation of the PCR results, since they include all populations of cells that reside in the brain and may include highly damaged DNA.

    Although controversial findings exist, this study emphasizes the importance of the mitochondrial hypothesis in AD pathophysiology. More studies must be done to clarify the role and the place of mitochondria in the complex scenario of AD.

    References:
    Coskun PE, Beal MF, Wallace DC. Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication.
    Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10726-31. Epub 2004 Jul 09. Abstract

    Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA. Mitochondrial abnormalities in Alzheimer's disease. J Neurosci. 2001 May 1;21(9):3017-23. Abstract

    Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA. Gene regulation and DNA damage in the ageing human brain. Nature. 2004 Jun 24;429(6994):883-91. Epub 2004 Jun 09. Abstract

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  1. Promoter Bashing—Mitochondrial Ones Damaged in AD Brain