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Enzymes 1-secretase

Involvement of several proteolytic enzymes, secretases, is probably crucial for this process but other hypotheses, including, for example, cholinergic transmission or accumulation of metal ions, have also been considered. Future perspectives in this area concern the search for novel pharmaceuticals that cross the blood-brain barrier, without side effects (e.g., the dyskinesias of L-Dopa), or potent and selective inhibitors of improper cleavage of amyloid protein, or even stem cell therapy to restore neuronal cells. [Pg.333]

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. [Pg.1111]

These must be worthwhile objectives and the recent identification by a number of research groups (see Skovronsky and Lee 2000 for description and details) of P-secretase as the membrane-bound aspartyl protease (RACE), S-site APP cleaving enzyme, paves the way for developing possible chemical inhibitors of its activity for experimental and clinical evaluation, although that remains for the future. [Pg.391]

BACE-1 (p-secretase) is one of the enzymes involved in breaking down APP to produce Ap (amyloid p-peptide, Ap40>42), the protein that eventually oligomerizes to form Ap plaques, the hallmark of Alzheimer s disease (AD). Thus an agent that... [Pg.206]

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. [Pg.233]

There are three genes believed to be involved in the cutting of the amyloids one gene encodes for the APP while two encode the enzymes P-secretase and y-secretase. [Pg.387]

Vassar, R. (2004) BACEl the beta-secretase enzyme in Alzheimer s disease. J. Mol. Neurosci., 23, 105-114. [Pg.334]

Spoelgen, R., von Arnim, C.A., Thomas, A.V., et al. (2006) Interaction of the cytosolic domains of sorLA/LRll with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme. J. Neurosci., 26, 418-428. [Pg.351]

A protein known as the amyloid precursor protein (APP) spans the plasma membrane of the neurone. It possesses an extracellular domain but its function is unknown. The extracellular domain is partially hydrolised by proteolytic enzymes, known as secretases. One of the products is the amyloid peptide, of which there are two forms. The larger form, contains 42 amino acids and readily polymerises to form plaques in the extracellular space, damaging the neurones. Some sufferers possess a mutated form of the APP protein which more readily produces the larger peptide upon proteolysis, so that more toxic plaques are produced. It is the progressive accumulation of these plaques that is considered to be one cause of Alzheimer s disease. [Pg.322]

PS-2, are found as the most frequent causes of early onset familial AD cases [5]. The prese-nilins are involved in APP processing by enzymes called secretases [6]. [Pg.25]

The protease [APP secretase) responsible for the normal cleavage of APP through the PA4 segment is unknown, but a number of proteases, including calpain [D. H. Small et al. 1992), a serine protease, and cathepsin B [Cataldo et al. 1991), have been proposed. It remains to be determined whether therapy should be directed at enhancing the function of the secretase to accelerate the breakdown of the PA4 segment or at inhibiting the enzyme to reduce APP turnover. [Pg.505]


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See also in sourсe #XX -- [ Pg.267 ]




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