Paradoxical Condensation of Copper with Elevated beta-Amyloid in Lipid Rafts under Cellular Copper Deficiency Conditions: IMPLICATIONS FOR ALZHEIMER DISEASE Export

@article{Hung_JBiolChem09, abstract = {Redox-active copper is implicated in the pathogenesis of Alzheimer disease (AD), {beta}-amyloid peptide (A{beta}) aggregation, and amyloid formation. A{beta}{middle dot}copper complexes have been identified in AD and catalytically oxidize cholesterol and lipid to generate H2O2 and lipid peroxides. The site and mechanism of this abnormality is not known. Growing evidence suggests that amyloidogenic processing of the {beta}-amyloid precursor protein (APP) occurs in lipid rafts, membrane microdomains enriched in cholesterol. {beta}- and {gamma}-secretases, and A{beta} have been identified in lipid rafts in cultured cells, human and rodent brains, but the role of copper in lipid raft amyloidogenic processing is presently unknown. In this study, we found that copper modulates flotillin-2 association with cholesterol-rich lipid raft domains, and consequently A{beta} synthesis is attenuated via copper-mediated inhibition of APP endocytosis. We also found that total cellular copper is associated inversely with lipid raft copper levels, so that under intracellular copper deficiency conditions, A{beta}{middle dot}copper complexes are more likely to form. This explains the paradoxical hypermetallation of A{beta} with copper under tissue copper deficiency conditions in AD. 10.1074/jbc.M109.019521}, author = {Hung, Ya H. and Robb, Elysia L. and Volitakis, Irene and Ho, Michael and Evin, Genevieve and Li, Qiao-Xin and Culvenor, Janetta G. and Masters, Colin L. and Cherny, Robert A. and Bush, Ashley I.}, citeulike-article-id = {5414236}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M109.019521}, citeulike-linkout-1 = {http://www.jbc.org/cgi/content/abstract/284/33/21899}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19542222}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19542222}, day = {14}, doi = {10.1074/jbc.M109.019521}, journal = {J. Biol. Chem.}, keywords = {abeta, amyloid, copper, experimental, lipid-raft}, month = {August}, number = {33}, pages = {21899--21907}, posted-at = {2009-08-11 09:13:25}, priority = {2}, title = {Paradoxical Condensation of Copper with Elevated {beta}-Amyloid in Lipid Rafts under Cellular Copper Deficiency Conditions: IMPLICATIONS FOR ALZHEIMER DISEASE}, url = {http://dx.doi.org/10.1074/jbc.M109.019521}, volume = {284}, year = {2009} }

TY - JOUR ID - Hung_JBiolChem09 L3 - citeulike-article-id:5414236 N2 - Redox-active copper is implicated in the pathogenesis of Alzheimer disease (AD), {beta}-amyloid peptide (A{beta}) aggregation, and amyloid formation. A{beta}{middle dot}copper complexes have been identified in AD and catalytically oxidize cholesterol and lipid to generate H2O2 and lipid peroxides. The site and mechanism of this abnormality is not known. Growing evidence suggests that amyloidogenic processing of the {beta}-amyloid precursor protein (APP) occurs in lipid rafts, membrane microdomains enriched in cholesterol. {beta}- and {gamma}-secretases, and A{beta} have been identified in lipid rafts in cultured cells, human and rodent brains, but the role of copper in lipid raft amyloidogenic processing is presently unknown. In this study, we found that copper modulates flotillin-2 association with cholesterol-rich lipid raft domains, and consequently A{beta} synthesis is attenuated via copper-mediated inhibition of APP endocytosis. We also found that total cellular copper is associated inversely with lipid raft copper levels, so that under intracellular copper deficiency conditions, A{beta}{middle dot}copper complexes are more likely to form. This explains the paradoxical hypermetallation of A{beta} with copper under tissue copper deficiency conditions in AD. 10.1074/jbc.M109.019521 IS - 33 JF - J. Biol. Chem. EP - 21907 TI - Paradoxical Condensation of Copper with Elevated {beta}-Amyloid in Lipid Rafts under Cellular Copper Deficiency Conditions: IMPLICATIONS FOR ALZHEIMER DISEASE VL - 284 SP - 21899 KW - abeta KW - amyloid KW - copper KW - experimental KW - lipid-raft AU - Hung, Ya AU - Robb, Elysia AU - Volitakis, Irene AU - Ho, Michael AU - Evin, Genevieve AU - Li, Qiao-Xin AU - Culvenor, Janetta AU - Masters, Colin AU - Cherny, Robert AU - Bush, Ashley PY - 2009/08/14/ UR - http://dx.doi.org/10.1074/jbc.M109.019521 ER -