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Zhang Q, Powers ET, Nieva J, Huff ME, Dendle MA, Bieschke J, Glabe CG, Eschenmoser A, Wentworth P, 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. PubMed.
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Case Western Reserve University
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.
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