Paradoxical condensation of copper with elevated beta-amyloid in lipid rafts under cellular copper deficiency conditions: implications for Alzheimer disease.
Redox-active copper is implicated in the pathogenesis of Alzheimer disease (AD), beta-amyloid peptide (Abeta) aggregation, and amyloid formation. Abeta.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 Abeta 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 Abeta 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, Abeta.copper complexes are more likely to form. This explains the paradoxical hypermetallation of Abeta with copper under tissue copper deficiency conditions in AD.
Hung
Ya Hui
YH
Oxidation Biology Laboratory, Victoria 3052, Australia; Centre for Neuroscience, Victoria 3010, Australia.
Robb
Elysia L
EL
Oxidation Biology Laboratory, Victoria 3052, Australia.
Volitakis
Irene
I
Oxidation Biology Laboratory, Victoria 3052, Australia; Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
Ho
Michael
M
Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
Evin
Genevieve
G
Department of Pathology, The University of Melbourne, Victoria 3010, Australia; The Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia.
Li
Qiao-Xin
QX
Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
Culvenor
Janetta G
JG
Centre for Neuroscience, Victoria 3010, Australia; Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
Masters
Colin L
CL
Department of Pathology, The University of Melbourne, Victoria 3010, Australia; The Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia.
Cherny
Robert A
RA
Oxidation Biology Laboratory, Victoria 3052, Australia.
Bush
Ashley I
AI
Oxidation Biology Laboratory, Victoria 3052, Australia; Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D003300:Copper / Q000172:deficiency* / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004705:Endocytosis; D005786:Gene Expression Regulation; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological
D016229:Amyloid beta-Peptides; D018076:DNA, Complementary; D003300:Copper; D002784:Cholesterol