Amyloid diseases efficiency

The 140-residue protein AS is able to form amyloid fibrils and as such is the main component of protein inclusions involved in Parkinson s disease. Full-length 13C/15N-labelled AS fibrils and AS reverse-labelled for two of the most abundant amino acids, K and V, were examined by homonuclear and heteronuclear 2D and 3D NMR.147 Two different types of fibrils display chemical shift differences of up to 13 ppm in the l5N dimension and up to 5 ppm for the backbone and side-chain 13C chemical shifts. Selection of regions with different mobility indicates the existence of monomers in the sample and allows the identification of mobile segments of the protein within the fibril in the presence of monomeric protein. At least 35 C-terminal residues are mobile and lack a defined secondary structure, whereas the N terminus is rigid starting from residue 22. In addition, temperature-dependent sensitivity enhancement is also noted for the AS fibrils due to both the CP efficiency and motional interference with proton decoupling.148... 

Currently the only specific pharmacological therapeutic option available for AD patients is treatment with cholinesterase inhibitors, which provide moderate benefits in a subset of patients for a limited period [7]. More efficient future therapeutic strategies may be directed at the metabolic events resulting in Ap accumulation, for example by inhibition of P- or y-sec-retase [7], or at the prevention of neuronal loss by neurotrophin therapy [6]. The availability of transgenic mouse models of the disease, such as mice overexpressing APP mutants [8], and the utilization of primate models of cerebral amyloid [9] permits preclinical testing of novel diagnostic and therapeutic approaches. 

X-Protein. Amyloid p i 42 peptide and r-protein have a clinical significance as early diagnostic markers in Alzheimer s disease (AD), and its evaluation is mandatory for efficient treatment. The mean levels of A/3i 42 and r-protein in CSF were significantly reduced (with high specificity and sensitivity) in patients in comparison to normal findings (M6). 

Amyloid Fibers in Disease Several small aromatic molecules, such as phenol red (used as a nontoxic drug model), have been shown to inhibit the formation of amyloid in laboratory model systems. A goal of the research on these small aromatic compounds is to find a drug that would efficiently inhibit the formation of amyloid in the brain in people with incipient Alzheimer s disease. 

Not all protein aggregates are beneficial. In patients afflicted with sickle-cell anemia, hemoglobin molecules aggregate into rods, rendering the red blood cell unable to transport O2 efficiently. Also, the presence of aggregates of proteins in the brain appears to be associated with severed serious conditions. For example, the amyloid plaques found in postmortem analysis of the brains of patients with Alzheimer s disease are a mixture of damaged neurons and aggregates of the fi amyloid protein, which is an extended antiparallel p sheet. 

FIGURE 8.5 Structuration of an IDP upon binding to membrane lipids. When an IDP comes close to a membrane, specific interactions with selected lipids (such as gangliosides in lipid rafts) will favor the efficient adhesion of the protein to this membrane. Moreover, the repetitive head groups of raft lipids wiU induce a-helical folding of the protein through a typical chaperone-facilitated reaction. The reduction of dimensionality from 3D (extracellular milieu) to 2D (hpid raft surface) also favors the concentration of the protein on the membrane surface. The Parkinson s and Alzheimer s disease-associated proteins a-synuclein and p-amyloid peptides (Ap) are typical examples of such IDPs that acquire a helical structure when bound to hpid rafts of neural cells. 

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