. Metabolite-initiated protein misfolding may trigger Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4752-7. PubMed.


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  1. Embalming Amyloid-β: The Role for Aldehyde Stress in Alzheimer's Disease

    Zhang and colleagues present novel findings demonstrating that cholesterol derivative-aldehydes resulting from ozonolysis can accelerate the aggregation of Aβ into fibers. This finding importantly extends earlier work showing that aldehydes from lipid peroxidation (Sayre et al., 1997; Takeda et al., 2000; Gómez-Ramos et al., 2003; Pocernich and Butterfield, 2003; Woltjer et al., 2003) and glycation (Smith et al., 1994) play a pivotal role in the genesis of AD pathology.

    Oxidative damage to lipids results in the production of several reactive aldehydes that can attack and modify DNA (Marnett, 2002; Luczaj and Skrzydlewska, 2003), proteins (Wataya et al., 2002; Zhang et al., 2003), lipids, and sugars (Woltjer et al., 2003). Aldehyde modifications may contribute to changes of biomolecule properties in two distinct ways: 1) render biomolecules more hydrophobic and 2) potentiate protein crosslinks. These alterations predispose to the occurrence of protein misfolding processes that accumulate during aging and age-related processes such as AD.

    Among common reactive aldehydes, 4-hydroxy-2-nonenal (HNE) is probably the most widely studied (Sayre et al., 1997; Takeda et al., 2000; Uchida, 2000; Wataya et al., 2002; Dianzani, 2003; Liu et al., 2003). It is considered one of the most neurotoxic aldehydes produced in vivo (Montine et al., 1996) and is a highly reactive electrophile that can form adducts onto several nucleophilic groups on biomacromolecules (Liu et al., 2003). In oxidative stress conditions, HNE accumulates in membranes at concentrations from 10 µM to 1 mM (Dianzini, 2003).

    Recent studies demonstrated that HNE promotes the increase of intracellular Aβ protein production, probably via the induction of BACE expression and activity (Tamagno et al., 2002). However, it seems that HNE also affects tau protein and, therefore, may play an important role in neurofibrillary degeneration. The new data presented by Zhang et al. alert us to the existence of other potentially deleterious aldehydes that can be produced in vivo (hypercholesterolemia and inflammation) and have an environmental source. These cholesterol derivate-aldehydes resulting from ozonolysis are worthy of further investigation.

    Dianzani MU. 4-hydroxynonenal from pathology to physiology. Mol Aspects Med 2003;24:263-272. Abstract

    Gomez-Ramos A, Diaz-Nido J, Smith MA, Perry G, Avila J. Effect of the lipid peroxidation product acrolein on tau phosphorylation in neural cells. J Neurosci Res. 2003 Mar 15;71(6):863-70. Abstract

    Liu Q, Raina AK, Smith MA, Sayre LM, Perry G. Hydroxynonenal, toxic carbonyls, and Alzheimer disease. Mol Aspects Med. 2003 Aug-Oct;24(4-5):305-13. Abstract

    Luczaj W, Skrzydlewska E. DNA damage caused by lipid peroxidation products. Cell Mol Biol Lett. 2003;8(2):391-413. Abstract

    Marnett LJ. Oxy radicals, lipid peroxidation and DNA damage. Toxicology. 2002 Dec 27;181-182:219-22. Review. Abstract

    Montine TJ, Amarnath V, Martin ME, Strittmatter WJ, Graham DG. E-4-hydroxy-2-nonenal is cytotoxic and cross-links cytoskeletal proteins in P19 neuroglial cultures. Am J Pathol. 1996 Jan;148(1):89-93. Abstract

    Pocernich CB, Butterfield DA. Acrolein inhibits NADH-linked mitochondrial enzyme activity: implications for Alzheimer's disease. Neurotox Res. 2003;5(7):515-20. Abstract

    Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, Smith MA. 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease. J Neurochem. 1997 May;68(5):2092-7. Abstract

    Smith MA, Taneda S, Richey PL, Miyata S, Yan SD, Stern D, Sayre LM, Monnier VM, Perry G. Advanced Maillard reaction end products are associated with Alzheimer disease pathology.
    Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5710-4. Erratum in: Proc Natl Acad Sci U S A 1995 Feb 28;92(5):2016. Abstract

    Takeda A, Smith MA, Avila J, Nunomura A, Siedlak SL, Zhu X, Perry G, Sayre LM. In Alzheimer's disease, heme oxygenase is coincident with Alz50, an epitope of tau induced by 4-hydroxy-2-nonenal modification. J Neurochem. 2000 Sep;75(3):1234-41. Abstract

    Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, Pronzato MA, Danni O, Smith MA, Perry G, Tabaton M. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis. 2002 Aug;10(3):279-88. Abstract

    Uchida K. 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Prog Lipid Res. 2003 Jul;42(4):318-43. Review. Abstract

    Wataya T, Nunomura A, Smith MA, Siedlak SL, Harris PL, Shimohama S, Szweda LI, Kaminski MA, Avila J, Price DL, Cleveland DW, Sayre LM, Perry G. High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal. J Biol Chem. 2002 Feb 15;277(7):4644-8. Epub 2001 Dec 03. Abstract

    Woltjer RL, Maezawa I, Ou JJ, Montine KS, Montine TJ. Advanced glycation endproduct precursor alters intracellular amyloid-beta/A beta PP carboxy-terminal fragment aggregation and cytotoxicity. J Alzheimers Dis. 2003 Dec;5(6):467-76. Abstract

    Zhang Q, Powers ET, Nieva J, Huff ME, Dendle MA, Bieschke J, Glabe CG, Eschenmoser A, Wentworth P Jr, Lerner RA, Kelly JW. Metabolite-initiated protein misfolding may trigger Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4752-7. Epub 2004 Mar 19. Abstract

    Zhang WH, Liu J, Xu G, Yuan Q, Sayre LM. Model studies on protein side chain modification by 4-oxo-2-nonenal. Chem Res Toxicol. 2003 Apr;16(4):512-23. Abstract

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  1. "Ozone Holes" in Human Brain? New Twists on Protein Folding