Amyloid beta: Difference between revisions
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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" /> | ||
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) is interrupted at the Ile32-Gly33 connection. The second helix corresponds to the | 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) is interrupted at the Ile32-Gly33 connection. The second helix 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/1'>kink</scene> (residues 26 and 27).<ref name="structure" /> | ||
The toxicity of amyloid beta is due to the formation of aggregates and oligomers. The actual structures of these oligomers is unknown but is likely similar to that of amyloid beta in mature plaques.<ref name="structure" /> | The toxicity of amyloid beta is due to the formation of aggregates and oligomers. The actual structures of these oligomers is unknown but is likely similar to that of amyloid beta in mature plaques.<ref name="structure" /> | ||
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'''Pore Formation''' | '''Pore Formation''' | ||
Amyloid beta can adhere to endothelial cell walls and create lesions, eventually a large | Amyloid beta can adhere to endothelial cell walls and create lesions, eventually a large deposit will cause cerebral hemorrhage. The pores cause loss of calcium homeostasis and an influx of Ca2+ into neurons.<ref name="alz" /> | ||
'''Interaction with tau''' | '''Interaction with tau''' | ||
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'''Binding ApoE''' | '''Binding ApoE''' | ||
Apolipoprotein E is normally involved in lipoprotein metabolism and transfer but it has been shown to play a role in the development of | Apolipoprotein E is normally involved in lipoprotein metabolism and transfer but it has been shown to play a role in the development of Alzheimer's. ApoE4 has the most affinity for amyloid beta and uses the low-density lipoprotein-related protein receptor to internalize amyloid beta into neurons it also promotes the production od amyloid beta by stimulating APP recycling. It is also theorized that apolipoproteins promote the aggregation of amyloid beta into toxic oligomers.<ref name="alz" /> | ||
'''Binding ABAD''' | '''Binding ABAD''' | ||
Amyloid beta-peptide binding alcohol dehydrogenase (ABAD) is an enzyme belonging to a family of short chain dehyndrogenase/reductases.<ref>Amyloid β-Peptide-binding Alcohol Dehydrogenase Is a Component of the Cellular Response to Nutritional Stress: Yan, Shi Du et al.'' (2000). [http://www.jbc.org/content/275/35/27100.full DOI: 10.1074/jbc.M000055200]</ref> When amyloid beta binds to ABAD in the mitochondria there is increased | Amyloid beta-peptide binding alcohol dehydrogenase (ABAD) is an enzyme belonging to a family of short chain dehyndrogenase/reductases.<ref>Amyloid β-Peptide-binding Alcohol Dehydrogenase Is a Component of the Cellular Response to Nutritional Stress: Yan, Shi Du et al.'' (2000). [http://www.jbc.org/content/275/35/27100.full DOI: 10.1074/jbc.M000055200]</ref> When amyloid beta binds to ABAD in the mitochondria there is increased mitochondrial dysfunction, increased reactive oxygen species and oxidative stress.<ref name="alz" /> It has been found that by inhibiting amyloid beta from binding ADAB, using a decoy peptide, oxygen consumption is increased and the toxic effect are decreased. <ref>Inhibition of Amyloid-beta (A beta) peptide-binding alcohol dehydrogenase-A beta interaction reduces A beta accumulation and improves mitochondrial function in a mouse model of Alzheimer's disease: Yao, Jen et al.'' (2006). [http://dx.doi.org/10.1523/JNEUROSCI.4717-10.2011]</ref> | ||
'''Binding Catalase''' | '''Binding Catalase''' | ||
Catalase normally functions to convert hydrogen peroxide to hydrogen and water. If amyloid beta complexes with catalase at residues 31-35 catalase can no longer breakdown the toxic molecule. Is it thought that the inactivation of catalase is due to the insertion of the sulfur side chain of methionine into the catalytic site.<ref name="alz" /> | |||
==Prevention== | ==Prevention== | ||
