A peptides

According to the amyloid hypothesis, the A 3 peptide plays a critical role in the pathogenesis of Alzheimer s disease [1]. Major forms of A 3 produced encompass 38, 40 or 42 residues. A 342 is more prone to aggregation than A 340 and in animal models an increased A[342/ A (340 ratio results in amyloid plaque pathology even when total A 3 levels are reduced [4]. The generation of A 3 is a normal process and A 3 is present in the brains and body fluids of humans throughout life. Neuronal... 

Alzheimer s Disease. Figure 2 A(3 is derived from the APP by the sequential action of proteolytic activities exerted by (3- and y-secretases. APP-CTF is (C99) produced after cleavage of the APP by (3-secretase and represents the substrate of the y-secretase. The yellow box marks membrane embedded amino acid residues of A(3 peptide. Scissors represent the main cleavage sites of (3- and y-secretase, e.g. the e- and y-cleavages at positions 49,46, 42, 40 and 38. 

The ECE isoforms show different subcellular distributions and enzymatic characteristics (Table 2). ECE-la and ECE-lc are mainly expressed at the cell surface, whereas ECE-lb, ECE-Id and ECE-2 are expressed intracellularly. Plasma membrane-bound ECE cleaves big-ET-1 circulating in the blood, whereas intracellular ECE isoforms are involved in the generation of mature endothelins. In addition, ECEs (as well as NEP and the insulin-degrading enzyme) contribute to the degradation of amyloid (3 (A 3) peptide. 

ECE isoforms are also involved in the degradation of A 3 peptide. A genetic variant of ECE-1 with an increased transcriptional activity is associated with a decreased risk for AD. Thus, the inhibition of ECE in the CNS may increase the risk for the development of Alzheimer s disease (AD). 

ET-1 from big-ET-1 by other proteases such as neutral endopeptidase or other currently unidentified proteases. Therefore, dual inhibition of ECE and NEP might inhibit ET-l generation more efficiently, than that seen for selective ECE inhibitors. However, dual inhibiton of ECE and NEP could also increase the risk for the development of AD, as both enzyme classes are involved in the degradation of A 3 peptide. 

Another competing cyclisation during peptide synthesis is the formation of aspartimides from aspartic acid residues [15]. This problem is common with the aspartic acid-glycine sequence in the peptide backbone and can take place under both acidic and basic conditions (Fig. 9). In the acid-catalysed aspartimide formation, subsequent hydrolysis of the imide-containing peptide leads to a mixture of the desired peptide and a (3-peptide. The side-chain carboxyl group of this (3-peptide will become a part of the new peptide backbone. In the base-catalysed aspartimide formation, the presence of piperidine used during Fmoc group deprotection results in the formation of peptide piperidines. 

Several pathological self-polymerizing systems have been biophysi-cally characterized sufficiently to permit identification of protein or peptide species that could serve as molecular targets in a structure-activity relationship. These include transthyretin (TTR) [73-76], serum amyloid A protein (SAA) [77], microtubule-associated protein tau [78-80], amylin or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis (AL) [83-85], polyglutamine diseases [9,86], a-synuclein [47,48] and the Alzheimer s (3 peptide [87-96]. A variety of A(3 peptide assay systems have been established at Parke-Davis to search for inhibitors of fibril formation that could be therapeutically useful [97]. 

In the search for fibril formation inhibitors, the self-association to form amyloid fibrils of the A(3 peptides containing 40 and 42 amino acids can be treated as a coupled protein folding and polymerization process passing through multiple intermediate peptide species. The in vitro challenge is (1) to identify the various conformational forms and... 

Cultured macrophages are able to rapidly refold A 3 peptide into its amyloidogenic conformation, which also supports the hypothesis that macrophages play a causal role in the generation of the plaque core [12,13]. Macrophage-facilitated refolding of amyloidogenic peptides... 

A small amount of AP antibody reaches the brain, binds to A(3 peptides, promotes the disassembly of fibrils, and, via the Fc antibody domain, encourages activated microglia to enter the affected region and remove A(3 [86] and/or... 

Morgan, D., Diamond, D. M., Gottschall, P. E. et al. A(3 peptide vaccination prevents memory loss in an animal model of Alzheimer s disease. Nature 408 982-985, 2000. 

Some generic structures of /3-amino acids are shown in Fig. 6.40. Since, in /3-amino acids, two C-atoms separate the amino and carboxylate groups, there are two possible locations for attachment of a single side chain (i.e., /32 and /33), or even two or more side chains (e.g., /32,3 and /32,2,3, respectively). In a /3-peptide, these symbols can be used as prefixes, e.g., the /33/32-dipeptide in Fig. 6.40 becomes /33-HAla- /32-HVal for R=Me and R = i-Pr. The stereodescriptors (R) and (S) should be used to specify the absolute configuration at the stereogenic centers. The same rules apply to y-amino acids and y-peptides. 

How does the ubiquitin-proteasome pathway contribute to pathogenesis of AD. It is thought that the causative factors in AD, namely, the A/3 peptide, or the paired helical filaments (PHF) of tau protein, impair proteasome function. In in vitro experiments, A/3 peptide has been shown to inhibit the proteasome. In the brains of AD patients, proteasome function has been shown to be reduced mostly in the areas critical for... 

A second example utilised a 3-peptide derivative (Fig. 5b). The elastic modulus could be varied from 4000 to 300 Pa (Table 2, entries 5-7), thus indicating that the ratio of enzyme to precursor plays a significant role in tailoring the supramolecular assemblies. 

The homo-polymer that results from the coupling of many Asp residues has also been shown to be of interest as a biodegradable polymer. Although most interest here involves the use of the mixed a-/ 3-peptide, the pure (3-peptide also has potential uses in the field. 

The mechanism of AD pathogenesis still remains unclear. However, one mechanism, amyloid (3 (A(3) accumulation, may be due to the disturbance in metal homeostasis in AD brains [Strausak et al., 2001]. A(3 peptides are the major constituents of the amyloid core of senile plaques, which are derived from the amyloid precursor protein (APP) and are secreted into extracelluar spaces. Both APP and A(3 contain a copper-binding domain [Hesse et al., 1994 Atwood et al., 1998]. High concentrations of copper, zinc, and iron have been found within the amyloid deposits in AD brains [Lovell et al., 1998], A(3 peptides can be rapidly precipitated by copper under mildly acidic conditions and by zinc at low physiological (submicromolar) concentrations [Bush et al., 1994], An age-dependent binding between A(3 peptides with excess brain metals (copper, iron, and zinc) induces A(3 peptides to precipitate into metal-enriched plaques [Bush, 2002],... 

Effects of Tea Extracts and Related Polyphenols against Toxicity Induced by A(3 Peptides... 

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