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- Title
Mercury Reduces the Enzymatic Activity of Neprilysin in Differentiated SH-SY5Y Cells.
- Authors
Chin-Chan, Miguel; Segovia, José; Quintanar, Liliana; Arcos-López, Trinidad; Hersh, Louis B.; Chow, K. Martin; Rodgers, David W.; Quintanilla-Vega, Betzabet
- Abstract
Levels of amyloid beta (Ab) 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 Ab in differentiated SH-SY5Y cells incubated with 1-20 μM of Hg. Exposure to 20 μM of Hg induced an increase in Aα-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 mM, and circular dichroismanalysis 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 lM) 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.
- Subjects
MERCURY poisoning; NEPRILYSIN; CELL differentiation; AMYLOID beta-protein; CENTRAL nervous system physiology; ALZHEIMER'S disease diagnosis
- Publication
Toxicological Sciences, 2015, Vol 145, Issue 1, p128
- ISSN
1096-6080
- Publication type
Article
- DOI
10.1093/toxsci/kfv037