Protein amyloid plaques

This disease develops when an abnormal prion protein present in the cadaveric material induces a cascade of conformational changes in host protein. Creutzfeldt-Jakob disease in recipients of somatropin differs from the sporadic form, in that it usually presents with cerebellar signs rather than cognitive impairment, and also in the prominence of prion protein amyloid plaques in nervous tissue (18). In a review, 139 cases of Creutzfeldt-Jakob disease were identified worldwide in people treated with cadaveric somatropin before recombinant human growth hormone became available in the mid-1980s (19). The prevalence of this fatal neurodegenerative condition in recipients of somatropin ranges from 0.3% in the USA to 4.4% in France. Creutzfeldt-Jakob disease has been reported to start at 4-30 years after therapy with cadaveric somatropin (18), so that further cases are anticipated and continue to be reported (20). 

Acute phase reactants (e.g., C-reactive protein) are proteins that increase during inflammation and are deposited in damaged tissues. They were first discovered in the serum, but are now known to be involved in inflammatory processes in the brain (e.g., found in the brain of Alzheimer patients and associated with amyloid plaques). 

Just like in coiled-coils, p-sheet secondary structure (Fig. 2) is ubiquitous in natural examples and in proteins and biomaterials. Alzheimer s disease is characterized by fibrillar amyloid plaques in the cerebral parenchyma. The insoluble amyloid fibrils are predominantly formed upon conformational switching of the 42 amino acid... 

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)...

A universal postmortem hallmark of Alzheimer s disease (AD) is the presence of amyloid plaques in the brain. These plaques are mainly composed of a 39 to 42 amino acid peptide, referred to as A0 peptide, that is excised from a precursor protein, amyloid precursor protein (APP), by the sequential action of two proteases (Olsen et al., 2001). The first of the two cleavages of APP occurs at a site within the APP protein that is termed the P-site, and BACE has been clearly determined to be the enzyme responsible for this cleavage event. A small portion of the AD patient... 

Abnormal phosphorylation of specific neural proteins may contribute to the development of Alzheimer s disease. Alzheimer s disease is a serious dementing illness of enormous medical and societal importance (see Ch. 47). It involves the degeneration of specific types of neuron in the brain. An invariable feature of Alzheimer s disease is the appearance of amyloid plaques. These plaques contain the A(3 amyloid protein, and there is some... 

Perutz, M. F., Pope, B. J., Owen, D., Wanker, E. E., and Scherzinger, E. (2002b). Aggregation of proteins with expanded glutamine and alanine repeats of the glutamine-rich and asparagine-rich domains of Sup35 and of the amyloid /1-peptide of amyloid plaques. Proc. Natl. Acad. Sci. USA 99, 5596-5600. 

Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., and Beyreuther, K. (1985). Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. USA 82, 4245—4249. 

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. 

Both amyloid plaques and the tangles of protein tau-containing paired helical filaments are typically present in Alzheimer disease. Which comes first ... 

Magaki et al. [2007] measured the levels of loosely bound, nonheme, and total iron and copper in the frontal cortex and hippocampus of patients with mild-moderate AD (n = 3), severe AD (n = 8), and dementia with Lewy bodies (DLB, n = 6). Additionally, the expression of iron regulatory protein 2 (IRP2) was examined in relation to the pathological hallmarks of AD, that is, 5 amyloid plaques, neurofibrillary tangles (NFT), and Lewy bodies. A significant decrease of loosely bound iron was found in the hippocampal white matter of both mild-moderate and severe AD patients and a trend toward increased... 

Figure 11.1 The amyloid hypothesis in Alzheimer s disease. The transmembrane protein amyloid precursor protein (APP) is cleaved first by f> -secretase (BACE), then by y -secretase. The resulting peptidic fragment, AfSAO/42, is liberated, leading to plaque accumulation. These plaques are associated with neuronal degeneration.

Alzheimer s disease (AD) is one of the most common forms of dementia that affect the elderly population. The histopathological hallmarks of AD are extracellular deposits known as neuritic amyloid plaques and intraneuronal inclusions composed of hyperphosphorylated tangles enriched with tau proteins.1 The principal component of the neuritic plaques is aggregation of amyloid (A0), which is likely to play a role in the neurodegenerative process. The relative contribution of the various forms (soluble dimers, small oligomers, protofibrils, and fibrils) of A0 to neuronal... 

Roher, A., Wolfe, D., Palutke, M. and KuKu-ruga, D. (1986) Purification, ultrastructure, and chemical analysis of Alzheimer disease amyloid plaque core protein. Proe Natl Aead Sci USA 83, 2662-2666. 

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