Amyloid beta: Difference between revisions
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<StructureSection load=1iyt size='500' side='right' caption='amyloid-beta(1-42)', ([[1dm0]])' scene=''> | <StructureSection load=1iyt size='500' side='right' caption='amyloid-beta(1-42)', ([[1dm0]])' scene=''> | ||
==Introduction== | ==Introduction== | ||
'''Alzheimer's disease''' is characterized by extracellular proteic plaques and intracellular neurofibril tangles.<ref name="structure">PMID: 12423364</ref> These plaques are collections of beta-amyloid <scene name='Amyloid_beta/Fibrils/1'>fibrils</scene> of beta-sheets. The fibrils form when normally soluble amyloid beta proteins reach a critical concentration and become insoluble, misfold, and aggregate.<ref name="stuff">PMID:22108203</ref> In the presence of oxygen and metal ions amyloid beta produces reactive oxygen species (especially hydrogen peroxide) in the absence of such molecules it can induce pore formation in neuronal and endothelial cells, triggering cell death.<ref name="structure" /><ref name="alz">PMID:18305836</ref> Yet another source of amyloid beta toxicity stems from its ability to induce endothelial cell damage through the production of superoxide, though the mechanism of such induction is unclear.<ref name="alz" /> While the presence of the fibril plaques remains a marker for Alzheimer's disease recent studies have suggested that alymoild beta oligomers most | '''Alzheimer's disease''' is characterized by extracellular proteic plaques and intracellular neurofibril tangles.<ref name="structure">PMID: 12423364</ref> These plaques are collections of beta-amyloid <scene name='Amyloid_beta/Fibrils/1'>fibrils</scene> of beta-sheets. The fibrils form when normally soluble amyloid beta proteins reach a critical concentration and become insoluble, misfold, and aggregate.<ref name="stuff">PMID:22108203</ref> In the presence of oxygen and metal ions amyloid beta produces reactive oxygen species (especially hydrogen peroxide) in the absence of such molecules it can induce pore formation in neuronal and endothelial cells, triggering cell death.<ref name="structure" /><ref name="alz">PMID:18305836</ref> Yet another source of amyloid beta toxicity stems from its ability to induce endothelial cell damage through the production of superoxide, though the mechanism of such induction is unclear.<ref name="alz" /> While the presence of the fibril plaques remains a marker for Alzheimer's disease, recent studies have suggested that alymoild beta oligomers' most devastating effect is the impairment of long-term potentiation which decreases dendritic spine density in the hippocampal brain and impairs memory.<ref name="recent">PMID:22114742</ref> | ||
==Structure== | ==Structure== | ||
Amyloid beta is actually the <scene name='Amyloid_beta/C-term/1'>C-terminal</scene> of the <scene name='Amyloid_beta/App/1'>Amyloid Precursor Protein</scene> which is a type I membrane-spanning glycoprotein encoded on chromosome 21 [[http://proteopedia.org/wiki/index.php/Amyloid_precursor_protein APP]].<ref name="alz" /> Amyloid beta results from an abnormal cleavage by [http://proteopedia.org/wiki/index.php/Beta_secretase beta-secretase] at the N-terminal and gamma-secretase at the C-terminal[[http://en.wikipedia.org/wiki/Beta_amyloid]]. The cleavage is nonspecific and results in peptides 39-43 amino acids in length, with 42 being the most common. Such cleavages occur most commonly in the plasma membrane though it can also occur in neuronal membranes.<ref name="alz" /> | |||
The first 16 residues, Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu--Val-His-His-Gln-Lys, are mostly hydrophobic with <scene name='Amyloid_beta/Cu/1'>His13 and His14</scene> acting as a binding domain for Cu(II). Residues <scene name='Amyloid_beta/Self/2'>12-23</scene> function as the self recognition region allowing for the formation of dimers and/or oligomers. This region also serves as the binding site for cholesterol, apolipoproteinE, alpha7nAChr, and amyloid beta-peptide binding alcohol dehydrogenase.<ref name="alz" /> | The first 16 residues, Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu--Val-His-His-Gln-Lys, are mostly hydrophobic with <scene name='Amyloid_beta/Cu/1'>His13 and His14</scene> acting as a binding domain for Cu(II). Residues <scene name='Amyloid_beta/Self/2'>12-23</scene> function as the self recognition region allowing for the formation of dimers and/or oligomers. This region also serves as the binding site for cholesterol, apolipoproteinE, alpha7nAChr, and amyloid beta-peptide binding alcohol dehydrogenase.<ref name="alz" /> | ||