title: Mercury Reduces the Enzymatic Activity of Neprilysin in Differentiated SH-SY5Y Cells.
abstract: Levels of amyloid beta (Aβ) in the central nervous system are regulated by the balance between its synthesis and degradation. Neprilysin (NEP) is associated with Alzheimer's disease (AD) by its ability to degrade Aβ. Some studies have involved the exposure to mercury (Hg) in AD pathogenesis; therefore, our aim was to investigate the effects on the anabolism and catabolism of Aβ in differentiated SH-SY5Y cells incubated with 1-20 μM of Hg. Exposure to 20 µM of Hg induced an increase in Aβ-42 secretion, but did not increase the expression of the amyloid precursor protein (APP). Hg incubation (10 and 20 µM) increased NEP protein levels; however, it did not change NEP mRNA levels nor the levels of the amyloid intracellular domain peptide, a protein fragment with transcriptional activity. Interestingly, Hg reduced NEP activity at 10 and 20 µM, and circular dichroism analysis using human recombinant NEP showed conformational changes after incubation with molar equivalents of Hg. This suggests that the Hg-induced inhibition of NEP activity may be mediated by a conformational change resulting in reduced Aβ-42 degradation. Finally, the comparative effects of lead (Pb, 50 μM) were evaluated. We found a significant increase in Aβ-42 levels and a dramatic increase in APP protein levels; however, no alteration in NEP levels was observed nor in the enzymatic activity of this metalloprotease, despite the fact that Pb slightly modified the rhNEP conformation. Overall, our data suggest that Hg and Pb increase Aβ levels by different mechanisms.
authors: *Department of Toxicology, Ave. IPN 2508, Colonia Zacatenco, Mexico City 07360, Department of Physiology, Biophysics and Neuroscience, Department of Chemistry, CINVESTAV, Mexico City 07360 and Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Biomedical Biological Sciences Research Building, 741 South Limestone St., Lexington, Kentucky 40536-0509.
authors: Miguel
authors: M
authors: Chin-Chan
authors: *Department of Toxicology, Ave. IPN 2508, Colonia Zacatenco, Mexico City 07360, Department of Physiology, Biophysics and Neuroscience, Department of Chemistry, CINVESTAV, Mexico City 07360 and Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Biomedical Biological Sciences Research Building, 741 South Limestone St., Lexington, Kentucky 40536-0509.
authors: José
authors: J
authors: Segovia
authors: *Department of Toxicology, Ave. IPN 2508, Colonia Zacatenco, Mexico City 07360, Department of Physiology, Biophysics and Neuroscience, Department of Chemistry, CINVESTAV, Mexico City 07360 and Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Biomedical Biological Sciences Research Building, 741 South Limestone St., Lexington, Kentucky 40536-0509.
authors: Liliana
authors: L
authors: Quintanar
authors: *Department of Toxicology, Ave. IPN 2508, Colonia Zacatenco, Mexico City 07360, Department of Physiology, Biophysics and Neuroscience, Department of Chemistry, CINVESTAV, Mexico City 07360 and Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Biomedical Biological Sciences Research Building, 741 South Limestone St., Lexington, Kentucky 40536-0509.
authors: Trinidad
authors: T
authors: Arcos-López
authors: *Department of Toxicology, Ave. IPN 2508, Colonia Zacatenco, Mexico City 07360, Department of Physiology, Biophysics and Neuroscience, Department of Chemistry, CINVESTAV, Mexico City 07360 and Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Biomedical Biological Sciences Research Building, 741 South Limestone St., Lexington, Kentucky 40536-0509.
authors: Louis B
authors: LB
authors: Hersh
authors: *Department of Toxicology, Ave. IPN 2508, Colonia Zacatenco, Mexico City 07360, Department of Physiology, Biophysics and Neuroscience, Department of Chemistry, CINVESTAV, Mexico City 07360 and Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Biomedical Biological Sciences Research Building, 741 South Limestone St., Lexington, Kentucky 40536-0509.
authors: K Martin
authors: KM
authors: Chow
authors: *Department of Toxicology, Ave. IPN 2508, Colonia Zacatenco, Mexico City 07360, Department of Physiology, Biophysics and Neuroscience, Department of Chemistry, CINVESTAV, Mexico City 07360 and Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Biomedical Biological Sciences Research Building, 741 South Limestone St., Lexington, Kentucky 40536-0509.
authors: David W
authors: DW
authors: Rodgers
authors: *Department of Toxicology, Ave. IPN 2508, Colonia Zacatenco, Mexico City 07360, Department of Physiology, Biophysics and Neuroscience, Department of Chemistry, CINVESTAV, Mexico City 07360 and Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Biomedical Biological Sciences Research Building, 741 South Limestone St., Lexington, Kentucky 40536-0509 mquintan@cinvestav.mx.
authors: Betzabet
authors: B
authors: Quintanilla-Vega
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D006801:Humans; D008628:Mercury / Q000633:toxicity*; D015260:Neprilysin / Q000378:metabolism*
chemical_list: D015260:Neprilysin; D008628:Mercury
keywords: Alzheimer’s disease; amyloid precursor protein; beta-amyloid peptide; lead; mercury; neprilysin; retinoic acid