Amyloid proteins aggregation

P Amyloid protein aggregation, leading to formation of plaques / Hyperphosphorylation of tau protein, leading to intracellular NFT development and collapse of microtubules / Inflammatory processes—levels of multiple cytokines and chemokines are elevated in AD brains / Neurovasculature dysfunction / Oxidative stress / Mitochondrial dysfunction... 

Amyloid-forming proteins, mainly in native state a-helical proteins undergoing a-helix to /1-strand conversion before or during fibril formation. Partially unfolded or misfolded /1-sheet fragments are discussed as precursors of amyloids. Protein aggregation combined with other events leads to the deposition of insoluble protein... 

Bucciantini M, Calloni G, Chiti F, Formigli L, Nosi D, Dobson CM, Stefani M (2004) Pre-fibrillar amyloid protein aggregates share common features of cytotoxicity. J Biol Chem 279 31374—31382 Bunn CW, Gamer EV (1947) The crystal stmeture of two polyamides ( nylons ). Proc R Soc Lond Ser A 189 39-68... 

Cheng, X. and van Breemen, R.B. (2005) Mass spectrometry-based screening for inhibitors of beta-amyloid protein aggregation. Anal, Chem., 77, 7012-7015. 

Thirunavukkuarasu, S. Jares-Eiijman, E. A. Jovin, T. M. Multiparametric fluorescence detection of early stages in the amyloid protein aggregation of pyrene-labeled a-synuclein. J. Mol. Biol. 2008, 378, 1064-1073. 

Figure 18.2 Production of senile plaque (S/A4 amyloid protein. Amyloid fS4 protein (/S/A4) is part of a 695, 751 or 770 amino-acid amyloid precursor protein APP. This is a transmembrane protein which is normally cleared within the fi/A4 amino acid sequence to give short 40 amino-acid soluble derivatives. It seems that under some circumstances as in Alzheimer s disease, APP is cleared either side of the fi/A4 sequence to release the 42/43 amino acid P/A4 which aggregates into the amyloid fibrils of a senile plaque (a). (See also Fig. 18.5.) Some factors, e.g. gene mutation, must stimulate this abnormal clearage leading to the deposition of P/A4 amyloid protein as plaques and tangles and the death of neurons (b)...

Pike, C.J., Walencewicz, A.J., Glabe, C.G. and Cotman, C.W. (1991). Aggregation-related toxicity of synthetic /3-amyloid protein in hippocampal cultures. Eur. J. Pharmacol. 207, 367-368. 

Neuritic or senile plaques are extracellular protein deposits of fibrils and amorphous aggregates of P-amyloid protein.11 This formed protein is central to the pathogenesis of AD. The P-amyloid protein is present in a non-toxic, soluble form in human brains. In AD, conformational changes occur that render it insoluble and cause it to deposit into amorphous diffuse plaques associated with dystrophic neuritis.14 Over time, these deposits become compacted into plaques and the P-amyloid protein becomes fibrillar and neurotoxic. Inflammation occurs secondary to clusters of astrocytes and microglia surrounding these plaques. 

Tomiyama T, Shoji A, Kataoka K, Suwa Y, Asano S, Kaneko H, Endo N. Inhibition of amyloid beta protein aggregation neurotoxicity by rifampicin. Its possible function as a hydroxyl radical scavenger. J Biol Chem 1996 271 6839-6844. 

Volume 309. Amyloid, Prions, and Other Protein Aggregates Edited by Ronald Wetzel... 

Fink A. Protein aggregation folding aggregates, inclusion bodies and amyloid. Fold. Des. 1998 3 R9-23. 

In any case, through the propensity and specificity for aggregation (e.g., by jS-sheet formation in amyloids), proteins, silk, or otherwise, they will precipitate and form disordered aggregates or fibrils under the appropriate conditions (whether in vivo or in vitro Dobson, 1992 Fandrich et al., 2001 Uversky and Fink, 2004). 

Amyloid in the original medical sense of the term refers to certain disease-related protein aggregates (Westermark et al., 2005). Nowadays, it is applied more broadly to protein aggregates that have certain biophysical and biochemical properties in common. The original amyloids have been found to consist mainly of polymerized fragments of about 20 different proteins, each amyloid containing one of these polypeptides. More recently, it has emerged that many other proteins may be converted into amyloid artificially under in vitro conditions that involve prior denaturation (Chiti et al., 1999 Stefani and Dobson, 2003). 

Ripaud, L., Maillet, L., Immel-Torterotot, F., Durand, F., and Cullin, C. (2004). The [URE3] yeast prion results from protein aggregates that differ from amyloid filaments formed in vitro. J. Biol. Chem. 279, 50962-50968. 

Amyloid fibrils are elongated, insoluble protein aggregates deposited in vivo in amyloid diseases, and amyloid-like fibrils are formed in vitro from soluble proteins. Both of these groups of fibrils, despite differences in the sequence and native structure of their component proteins, share common... 

Tomiyama, T., Shoji, A., Kataoka, K., Suwa, Y., Asano, S., Kaneko, H., and Endo, N., Inhibition of amyloid beta protein aggregation and neurotoxicity by rifampicin its possible function as a hydroxyl radical scavenger, ]. Biol. Chem., 271, 6839,1996. 

Protein aggregation is a common feature of all of the chronic human neurode-generative disorders. The intraneuronal inclusions in many of these diseases contain deposits of ubiquitylated proteins, indicating that perturbations of ubiquitin-dependent proteolysis may occur. The neuropathological hallmarks of AD are intraneuronal NFTs composed of hyperphosphorylated protein tau and extracellular amyloid plaques (12,23,24,191,207). Most of the ubiquitylated, hyperphosphorylated tau protein in NETs is monoubiquitylated, with the remainder polyubiquitylated, as the substrate of the 26S proteasome (258). The protein deposits in NET, neuritic plaques, and neuropil threads in the cerebral cortex of AD patients and those with... 

CD has been used extensively in studies of peptides related to Alzheimers disease, although studies of the amyloid plaques associated with the disease are precluded by their insolubility. 211 A peptide consisting of 39-43 residues is the principal component of amyloid deposits that are found in the brains of Alzheimers patients. This peptide, called A4, 3-peptide, or 3AP for (3-amyloid peptide, is derived by proteolytic cleavage of a protein called amyloid protein (APP). The mechanism of aggregation of (3AP is clearly of great interest. 

Protein misfolding is most commonly caused by a gene mutation, which produces an altered protein. An example of this is the amyloid protein that spontaneously aggregates in many degenerative diseases, for example, Alzheimer disease. 

Figure 14.18 Structure of an amyloid fibril (a) and individual fibre (b) formed from insoluble protein aggregates the arrows represent p-sheet units (c) Structure of The HET-s (218-289) prion in its amyloid form obtained by solid-state NMR spectroscopy.31...

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