Transition metal‐mediated glycoxidation accelerates cross‐linking of β‐amyloid peptide

Abstract

b-Amyloid deposits, hallmarks of Alzheimer's disease, contain both sugar-derived`advanced glycation end products' (AGEs) and copper and iron ions. Our in vitro experiments using synthetic b-amyloid peptide and glucose or fructose show that formation of covalently cross-linked high-molecular-mass b-amyloid peptide oligomers is accelerated by micromolar amounts of copper (Cu 1 , Cu 21 ) and iron (Fe 21 , Fe 31 ) ions. Formation of these covalent AGE cross-links can be inhibited by capping agents of amino groups, redox-inactive metal chelators and antioxidants, suggesting that these drugs may be able to slow down the formation of insoluble b-amyloid deposits in vivo and possibly the progression of Alzheimer's disease.Keywords: advanced glycation end products; Alzheimer's disease; b-amyloid peptide; transition metals.Alzheimer's disease (AD) is a progressive dementia affecting a large proportion of the ageing population. Histological hallmarks of the disease are a regionally progressive loss of synaptic integrity and neuronal cell death, accompanied by the formation of amyloid plaques and neurofibrillary tangles [1]. The major proteinaceous component of the amyloid deposits is the b-amyloid peptide, which consists of 39±42 amino acids and is formed by proteolytic degradation of its precursor, the amyloid b precursor protein, in lysosomes and the endoplasmic reticulum [2,3].Although most patients with AD develop the sporadic and late-onset form, some show an obvious family history of the disease. In these families, mutations in three genes (the gene encoding the amyloid precursor protein and the presenilin 1 and 2 genes) have been discovered that account for nearly all earlyonset cases. These mutations influence b-amyloid peptide aggregation parameters, its concentration or the ratio of the 1±42 to 1±40 form, thus determining the rate of amyloid plaque formation [4,5]. It is commonly believed that the time course of amyloid plaque formation is one of the parameters that influences the time of onset or progression of the disease. Methods of minimizing b-amyloid peptide production and aggregation or interfering with its neurotoxic or pro-inflammatory effects are therefore expected to be of value in the prevention or treatment of AD [6,7].There is increasing evidence that the insolubility of b-amyloid plaques is caused by extensive covalent protein cross-linking [8]. One mechanism by which long-lived proteins can be cross-linked involves`advanced glycation end products' (AGEs) [9,10]. Formation of AGEs starts with non-enzymatic addition of a sugar or a sugar-fragmentation product to a protein, followed by rearrangement to a Schiff-base adduct and finally to a protein-bound Amadori product. AGEs are then formed through subsequent oxidations and dehydrations, including free-radical intermediates, and consist of a broad range of heterogeneous fluorescent and yellow-brown products including nitrogen-containing and oxygen-containing heterocycles (Fig. 1) [11,12].In particular, extracellular AGE formation in AD has been demon...

Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer’s disease

“…by glycation or oxidation) β-amyloid (Aβ) peptide, are present in specific brain regions of AD patients (Loske et al 2000;Thal et al 2002). Aβ has been proposed to have a variety of toxic properties such as the ability to block communication between neurons, to cause degeneration of neurites, to contribute to oxidative stress and ultimately to lead to neuronal cell death ).…”

LR-90 a new advanced glycation endproduct inhibitor prevents progression of diabetic nephropathy in streptozotocin-diabetic rats

“…Although aldose and ketose sugars were originally thought to be the sole precursors of AGE, current research indicate that RCS generated from carbohydrate, lipid and amino acid metabolisms such as MGO, GO, GLA, dehydroascorbate, 3-deoxyglucosone and malondialdehyde, are even more reactive and are potent precursors of AGE formation and protein cross-linking [6,7,8,9,10,54,55,56]. Known AGE inhibitors with renoprotective effects such AG, PM, and OPB-9195 are thought to prevent AGE accumulation by interacting with these highly reactive RCS and acting as carbonyl traps, thereby limiting oxidative damage to tissues.…”

“…Autooxidation of glucose and oxidation of glycated residues are potent sources of free radicals that are enhanced in hyperglycaemia and might be the primary culprits in tissue damage. These reactions are catalysed by low concentrations of transition metals, particularly iron and copper, which are normally in a bound state but whose homeostasis could be compromised by diabetes and Alzheimer's disease [8,9,10].…”

Inhibition of human muscle-specific enolase by methylglyoxal and irreversible formation of advanced glycation end products

“…AGEs are a significant factor in the pathogenesis of diabetes and diabetic complications, such as retinopathy, kidney dysfunction, cataract, and atherosclerosis [9 -12]. Accumulation of protein AGEs was also observed in neurodegenerative diseases [13,14].…”