Amyloid beta: Difference between revisions
Jump to navigation
Jump to search
Laura Olney (talk | contribs) No edit summary |
No edit summary |
||
| (13 intermediate revisions by 2 users not shown) | |||
| Line 1: | Line 1: | ||
<StructureSection load=1iyt size=' | <StructureSection load=1iyt size='350' side='right' caption="Amyloid-beta(1-42) [[1iyt]]" scene=''> | ||
==Introduction== | ==Introduction== | ||
' | [[Alzheimer's Disease|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, and trigger 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/ | Amyloid beta is actually the <scene name='Amyloid_beta/N-term/1'>N-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 | The first 16 residues, Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu--Val-His-His-Gln-Lys, are mostly hydrophillic 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 most reasonable structure determined structure consists of <scene name='Amyloid_beta/Structure/1'>two helices</scene>; the first helix (residues 8-25) is well defined and has an RMSD of 0.38 angstroms and the second (residues 28-38) corresponds to the trans-membrane region of APP and thus contains multiple small and hydrophobic amino acids. The two helices are connected by a <scene name='Amyloid_beta/Kink/3'>kink</scene> (residues 26 and 27).<ref name="structure" /> | The most reasonable structure determined structure consists of <scene name='Amyloid_beta/Structure/1'>two helices</scene>; the first helix (residues 8-25) is well defined and has an RMSD of 0.38 angstroms and the second (residues 28-38) corresponds to the trans-membrane region of APP and thus contains multiple small and hydrophobic amino acids. The two helices are connected by a <scene name='Amyloid_beta/Kink/3'>kink</scene> (residues 26 and 27).<ref name="structure" /> | ||
| Line 17: | Line 17: | ||
'''Generation of Radicals''' | '''Generation of Radicals''' | ||
Amyloid beta generates reactive oxygen species and induces oxidative stress and inflammation. When complexed with Cu(II) amyloid beta becomes a moderate oxidant that is capable | Amyloid beta generates reactive oxygen species and induces oxidative stress and inflammation. When complexed with Cu(II) amyloid beta becomes a moderate oxidant that is capable of creating hydrogen peroxide in the presence of air and a reducing agent (such as ascorbate).<ref name="alz" /> | ||
'''Toxicity in the Vasculature''' | |||
A build up of amyloid beta results in the oxidative stress, caspase activation, mitochondrial dysfunction and DNA damage. Once amyloid beta produces superoxide it can react with nitrogen oxide and cause vasoconstriction, decreasing the blood supply to the brain.<ref name="alz" /> | |||
'''Pore Formation''' | '''Pore Formation''' | ||