Mechanism for Amyloid-beta Accumulation in Alzheimer’s Disease
Rashid Deane, Ph.D.
University of Rochester
NIEHS Grant P30ES001247
An NIEHS grantee and colleagues report that low levels of copper can accumulate in the brain, leading to amyloid-beta plaques that are the hallmark of Alzheimer's disease. The research reveals the molecular mechanisms by which copper accelerates Alzheimer's disease and provides information that could be useful for developing preventative and/or therapeutic approaches to control neurotoxic amyloid-beta levels in the aging brain.
The researchers used normal mice, a mouse model of Alzheimer's disease, and human cells to study copper-induced amyloid-beta accumulation in the brain. In normal aging mice, they found that copper accumulated in brain capillaries, and the accumulation was associated with a decrease reduction in the amyloid-beta transporter known as low-density lipoprotein receptor-related protein 1 (LRP1), which normally removes amyloid-beta from the brain. The copper accumulation was also linked with higher brain amyloid-beta levels. In human brain endothelial cells, normal levels of copper caused LRP1 down-regulation. In the mouse model of Alzheimer's disease, copper accumulated in brain capillaries and, unlike in control mice, in the parenchyma. In the model mice, copper not only down-regulated LRP1 in brain capillaries but also increased amyloid-beta production and neuroinflammation.
Overall, this work demonstrated that copper’s effect on amyloid-beta homeostasis in the brain depends on whether it accumulates in capillaries or in the parenchyma.
Citation: Singh I, Sagare AP, Coma M, Perlmutter D, Gelein R, Bell RD, Deane RJ, Zhong E, Parisi M, Ciszewski J, Kasper RT, Deane R. 2013. Low levels of copper disrupt brain amyloid-beta homeostasis by altering its production and clearance. Proc Natl Acad Sci U S A 110(36):14771-14776.
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