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...

These findings suggest that factors other than removal are responsible for the lower pre-dialysis AGE levels found in patients on convective dialysis as well as on HD with UDF. A role of water quality is assumed. This is corroborated by the finding that the high molecular weight AGE-fraction is preferentially lowered in comparison with patients on HD with SDF, as analysed by gel filtration chromatography. These findings could be best explained by a less severe oxidative stress (i.e. resulting in decreased AGE generation) with HF and HDF, as well as with ultrapure HD.

This pilot study represents a landmark for the implementation of clinical pharmacy in daily practice especially on medical wards in Germany. Working in wards offers interns a possibility to extend their knowledge and skills. The project demonstrates that pharmacy interns can play an important role in drug safety in hospital wards. The acceptance by physicians and nurses is high. The majority of them requested the continuation of the project.