Alzheimer’s disease amyloid-P

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The consensus opinion is that, regardless of the causes of Alzheimer s disease, amyloid-P proteins are deposited in the brain and, together with tau proteins, form... 

Walter, M.F. Mason, P.E. Mason, R.P. Alzheimer s disease amyloid p peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem. Biophys. Res. Commun. 1997, 233, 760-764. 

Jia H, Jiang Y, Ruan Y, Zhang Y, Ma X, Zhang J, Beyreuther K, Tu P, Zhang D (2004) Tenuigenin treatment decreases secretion of the Alzheimer s disease amyloid P-protein in cultured cells. Neurosci Lett 367 123-128... 

AgyarC/ E.K./ Leonard, S.R., Curran, G.L., et al., 2013. Traffic jam at the blood-brain barrier promotes greater accumulation of Alzheimer s disease amyloid-p proteins in the cerebral vasculature. Mol. Pharmaceut. 10, 1557-1565. 

Mason, R. P., Estermyer, J. D., Kelly, J. F., and Mason, P. E. (1996). Alzheimer s disease amyloid // peptide 25-35 is localized in the membrane hydrocarbon core X-ray diffraction analysis. Biochem. Biophys. Res. Commun. 222, 78-82. 

Phiel, C.J., Wilson, C.A., Lee, V.M., Klein, P.S. (2003) GSK-3alpha regulates production of Alzheimer s disease amyloid-beta peptides. Nature, 423, 435-439. 

Marambaud, P., Zhao, H., Davies, P. (2005) Resveratrol promotes clearance of Alzheimer s disease amyloid- 3 peptides. J. Biol. Chem., 280, 37377-37382. 

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El-Agnaf OM, Bodies AM, Guthrie DJ, Harriott P, Irvine GB. The N-terminal region of non-A beta component of Alzheimer s disease amyloid is responsible for its tendency to assume beta-sheet and aggregate to form fibrils. 

Curtain, C.C., et al., Alzheimer s disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J Biol Chem, 2001. 276(23) p. 20466-73. 

General trends in radiopharmaceutical research emphasize the use of small peptides. These molecules, of which the agents mentioned for thrombosis localization are an example, exhibit rapid and specific binding, and rapid blood clearance, two important parameters for a successflil radiopharmaceutical. Peptides are readily labeled with Tc and lend themselves to formulation as lyophilized kits that can be rapidly and rehably reconstituted. Possible targets for these molecules are quite varied, ranging from atherosclerotic plaque to P-amyloid (for Alzheimer s disease), to a variety of somatic receptors the populations of which are increased or decreased in disease. 

Lyim and co-workers carried out smdies of the Ap(io 35) peptide - derived from residues 10-35 of the p-amyloid responsible for Alzheimer s disease - which forms fibrils composed of parallel p-sheets [62]. The peptide was compared to its C-terminal PEG-derivatised analogue. TEM experiments showed that both formed fibrils [63] (Fig. 21) but the uranyl acetate stain was not found inside the peptide-PEG fibrils, indicating that PEG was at the outer edge of the fibril. 

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 18.1 Typical tangle (T) and plaque (P) as visualised by silver impregnation in the cerebral cortex of a case of Alzheimer s disease. The extracellular plaque (10-50 pm diameter) consists of a central core of amyloid surrounded by glial processes and a number of neurites in a ring formation. The intracellular cytoplasmic tangle is composed of helical filaments in a paired format. (Reproduced with permission of Academic Press from Wischik and Crowther 1986)...

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)...

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