Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance
Whereas amyloid-β (Aβ) accumulates in the brain of normal animals dosed with low levels of copper (Cu), the mechanism is not completely known. Cu could contribute to Aβ accumulation by altering its clearance and/or its production. Because Cu homeostasis is altered in transgenic mice overexpressing A...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 36; pp. 14771 - 14776 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Washington, DC
National Academy of Sciences
03.09.2013
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | Whereas amyloid-β (Aβ) accumulates in the brain of normal animals dosed with low levels of copper (Cu), the mechanism is not completely known. Cu could contribute to Aβ accumulation by altering its clearance and/or its production. Because Cu homeostasis is altered in transgenic mice overexpressing Aβ precursor protein (APP), the objective of this study was to elucidate the mechanism of Cu-induced Aβ accumulation in brains of normal mice and then to explore Cu’s effects in a mouse model of Alzheimer’s disease. In aging mice, accumulation of Cu in brain capillaries was associated with its reduction in low-density lipoprotein receptor-related protein 1 (LRP1), an Aβ transporter, and higher brain Aβ levels. These effects were reproduced by chronic dosing with low levels of Cu via drinking water without changes in Aβ synthesis or degradation. In human brain endothelial cells, Cu, at its normal labile levels, caused LRP1-specific down-regulation by inducing its nitrotyrosination and subsequent proteosomal-dependent degradation due in part to Cu/cellular prion protein/LRP1 interaction. In APP ˢʷ/⁰ mice, Cu not only down-regulated LRP1 in brain capillaries but also increased Aβ production and neuroinflammation because Cu accumulated in brain capillaries and, unlike in control mice, in the parenchyma. Thus, we have demonstrated that Cu’s effect on brain Aβ homeostasis depends on whether it is accumulated in the capillaries or in the parenchyma. These findings should provide unique insights into preventative and/or therapeutic approaches to control neurotoxic Aβ levels in the aging brain. |
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Bibliography: | http://dx.doi.org/10.1073/pnas.1302212110 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Thomas C. Südhof, Stanford University School of Medicine, Stanford, CA, and approved July 18, 2013 (received for review February 2, 2013) Author contributions: R.D. designed research; I.S., A.P.S., M.C., D.P., R.G., R.D.B., R.J.D., E.Z., M.P., J.C., and R.T.K. performed research; I.S., A.P.S., M. C., D.P., R.G., R.D.B., R.J.D. and R.D. analyzed data; and R.D. wrote the paper. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1302212110 |