Amyloid- 3 plaques

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). 

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... 

The enzymes that are involved in the processing of APP into amyloid peptides are known as secretases. Beta-secretase is an enzyme that catalyzes the initial proteolytic event leading to the production of Abeta amyloid peptides. If APP is cleaved by beta-secretase it can then be further cleaved by gamma-secretase. Abeta peptides are either secreted or intracellularly released. They have varying lengths and represent intermediate degradation products of its precursor (i.e., (3-secretase cleaved APP). Especially the 42 amino acid peptide (A 342) aggregates to form insoluble 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... 

In fact no consistent correlation has been found between the appearance, distribution and number of amyloid plaques and either neuronal loss or the degree of dementia, although the latter correlates with the number of neurofibrillary tangles, which tend to precede plaques in appearance by some years. Also cortical amyloid deposits can be found in non-demented elderly patients. Thus the basic question appears to be does the disease process, whatever that is, cause the development of AzD as well as the production of jS-amyloid or is there production of S-amyloid, which then causes AzD Consensus supports the latter but it is not proven. 

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... 

Chen, G., Chen, K. S., Knox, J. et al. A learning deficit related to age and P-amyloid plaques in a mouse model of Alzheimer s disease. Nature 408 975-979,2000. 

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. 

Inhibiting the production of the Aft peptides represents the most direct approach to curtailing their potential to accumulate as amyloid plaques, by inhibiting either the ft-sec-retase at step 1 or the y-secretase at step 2. Because these are enzymatic reactions with measurable products, a biochemical assay using a purified enzyme preparation can be integrated into an HTS platform, facilitating the rapid evaluation of large numbers of compounds for inhibition of the enzymatic activity. 

Because conformational epitopes are not easily mimicked with linear peptides, which can elicit nonspecific antibodies, several alternative strategies such as synthetic cyclic peptides have been developed [see e.g., (18)]. A similar conformational restriction was seemingly achieved with a P-amyloid peptide that was anchored to the surface of liposomes via hydrophobic tails introduced at its both N- and C-termini. The reconstituted peptide proved highly immunogenic and elicited antibodies that could significantly prevent amyloid plaque formation in a model system (70). 

Nicolau C, et al. A liposome-based therapeutic vaccine against beta-amyloid plaques on the pancreas of transgenic NORBA mice. Proc Natl Acad Sci USA 2002 99 2332. 

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