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Beta Amyloid Peptides and Amyloidosis.

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10/09/2013

Beta Amyloid Peptides and Amyloidosis.

Amyloidosis refers to a variety of pathological conditions. All have one thing in common; normally soluble proteins become insoluble and are subsequentially deposited in the extracellular space of various organs or tissues where they disrupt normal cell function. Approximately 60 amyloid proteins have been identified so far. Alzheimer’s disease is one of the most common forms of senile dementia. Beta amyloid is believed to be a primary causative agent of Alzheimer’s disease, however, existing therapeutics focus on clearing out beta amyloid from the brain. The beta amyloid peptide contains 36 to 43 amino acids within it polypeptide sequence and is processed from the amyloid precursor protein. The beta-amyloid  peptides are generated as cleavage products from the membrane protein, amyloid precursor protein, by two proteases, ß-secretase and γ-secretase. Beta Amyloid peptides are amphiphilic peptides with a hydrophilic N-terminal domain (residues 1 to 28) and a hydrophobic C-terminal (residues 29 to 40), the latter corresponding to a part of the transmembrane domain of amyloid precursor protein. Amyloids are filamentous protein deposits ranging in size from nanometres to microns. These composites are composed of aggregated peptide beta-sheets formed from parallel or anti-parallel alignments of peptide beta-strands, and are also known as amyloid plaques in association with Alzheimer's disease. The beta eptide is the main component of certain deposits found in the brains of patients with Alzheimer's disease. Furthermore, evidence has been found that the amyloid beta amyloid peptide is a highly multifunctional peptide with significant non-pathological activity. In addition, amyloid-forming proteins have been found to be associated with over 30 diseases, such as neurodegenerative conditions like Alzheimer's, Huntington's, Parkinson's, Creutzfeldt-Jacob and prion disorders, but also systemic diseases, such as amyotrophic lateral sclerosis (Lou Gehrig's disease) and type II diabetes. The causative element of all these amyloidosis diseases is thought to involve important conformational changes in the proteins involved. The molecular phenomenon is called misfolding, hence, they are also sometimes termed as a “Misfolding-Disease.” Apparently amyloidosis appears to be a misfolding disease. This type of disease usually produces beta-sheet structures with a strong tendency to aggregate into water-insoluble fibrous polymers. Unfortunately, the exact reasons for these conformational changes in vivo are still unclear. In recent years, numerous in vitro studies of short and medium length peptides that form amyloids have provided some clues how amyloids are formed. It was found that an alpha-helix to beta-sheet folding transition occurs, which is sometimes implicated as the intermediary step leading to amyloid formation. Synthetic amyloid peptides are ideal candidates for in vitro studies to elucidate the mechanism of the alpha-helix to beta-sheet folding transition and to better understand Amyloidosisdiseases.

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