Beta-amyloid Fibres
What is it?
Amyloid –β protein (Aβ) is the main protein in the amyloid plaques of an Alzheimer's brain. There are two forms of Aβ, one with 40 aminoacids (Aβ40) and one with 42 aminoacids (Aβ42).
Amyloid fibrils are deposited extracellularly, and they can bind to the dye, Congo red, giving an ‘apple-green’ birefringence under polarized light (Figure 1).
What is it?
Amyloid –β protein (Aβ) is the main protein in the amyloid plaques of an Alzheimer's brain. There are two forms of Aβ, one with 40 aminoacids (Aβ40) and one with 42 aminoacids (Aβ42).
Amyloid fibrils are deposited extracellularly, and they can bind to the dye, Congo red, giving an ‘apple-green’ birefringence under polarized light (Figure 1).
According to Sawaya et al. (2007), the fibrils also present β-sheets parallel to the fibril axis. Due to their complementary peptide sequences, these sheets are able to bind to each other to form steric zipper structures. The structures are classified by (1) whether the sheets are parallel or antiparallel, (2) whether the sheets are packed with the same (‘face-to-face’) or different (‘face-to-back’) surfaces adjacent to one another, and (3) whether the sheets are oriented ‘up–up’ or ‘up–down’ with respect to one another. Combinations of these three structural arrangements give eight theoretically possible classes of steric zippers (Figure 2).
Aβ is a product of APP (amyloid precursor protein) cleavage by the two enzymes, β-and γ-secretases. First APP is cleaved by β-secretase to form a 99-amino-acid structure that is subsequently cleaved by γ-secretase (Figure 3). Depending on the point of cleavage, this forms a 40 or a 42-amino-acid structure (Irvine et al.,2008).
How was it discovered?
AD shows similarities to prion disorders (Spongiform Encephalopathies) such as Kuru (occurring in Fore tribesman of New Guinea), Creutzfeldt-Jakob Disease (CJD), Gerstmann-Straussler-Scheinker Syndrome (GSS) and Familial Fatal Insomnia. Prusiner (1990) discovered that these transmissible diseases were caused by the overproduction and accumulation of a mutant protein (PrPsc) that formed the amyloid plaques, similar to those present in AD patients’ brain tissues.
The gene that encodes APP is located on chromosome 21, and the connection between Aβ overproduction and dementia is strongly reinforced by the AD-like pathology observed in Down Syndrome.
The gene that encodes APP is located on chromosome 21, and the connection between Aβ overproduction and dementia is strongly reinforced by the AD-like pathology observed in Down Syndrome.
How is it implicated in AD?
Figure 4: The Aβ formation hypothesis and its implication in AD. It is thought that increased levels of Aβ leads to AD via toxic signalling cascade, which manifests as neuronal damages and neurofibrillary tangles.
According to Irvine et al. (2008), Aβ production is a natural process but its overproduction may cause accumulation. Consequently, oligomerized Aβ can lead to neuronal damages. Soluble Aβ is also related to AD because it appears to initiate a toxic signaling cascade that activates the kinases ERK2 and JNK1, which phosphorylate the tau protein, leading to neurofibrillary tangles (Figure 4).
How does it lead to BACE inhibitors?
Inhibition of β-secretase 1 (BACE 1) would reduce β-amyloid production and its aggregation, leading to diminished amyloid plaque formation.
Copyright ©2012 by SW Wong, E Lo and N Rodrigues. All rights reserved.
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