2017  0,977
2016  0,799
2015  0,662
2014  0,740
2013  0,739
2012  0,637
2011  0,658
2010  0,654
2009  0,570
2008  0,849
2007  0,805
2006  0,330
2005  0,435
2004  0,623
2003  0,567
2002  0,641
2001  0,490
2000  0,477
1999  0,762
1998  0,785
1997  0,507
1996  0,518
1995  0,502
Vol 52(2018) N 4 p. 590-597; DOI 10.1134/S0026893318040106 Full Text

S.A. Kozin1*, V.I. Polshakov2, Y.V. Mezentsev3, A.S. Ivanov3, S.S. Zhokhov2, M.M. Yurinskaya1,4, M.G. Vinokurov4 , A.A. Makarov1, V.A. Mitkevich1

Enalaprilat Inhibits Zinc-Dependent Oligomerization of Metal-Binding Domain of Amyloid-beta Isoforms and Protects Human Neuroblastoma Cells from Toxic Action of these Isoforms

1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia
2Faculty of Fundamental Medicine, Moscow State University, Moscow, 117192 Russia
3Orekhovich Institute of Biomedical Chemistry, Russian Academy of Sciences, Moscow, 119121 Russia
4Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow oblast, 142290 Russia

Received - 2017-11-24; Accepted - 2018-02-01

Intact amyloid-β peptides (Aβ) may undergo prion-like aggregation when they interact with chemically or structurally modified variants of Aβ present in extracellular pathohistological inclusions (amyloid plaques). This aggregation is regarded as one of the key molecular mechanisms of Alzheimer's disease (AD) pathogenesis. Zinc ions are involved in the pathological dimerization and oligomerization of natural Aβ isoforms, and zinc-induced oligomers can also initiate the pathological aggregation of Aβ. Based on the earlier found molecular mechanism of zinc-dependent oligomerization of Aβ, it has been suggested that the targeted inhibition of the 11EVHH14 site in one Aβ molecule from zinc-mediated interactions with the same site of another Aβ molecule can effectively inhibit the oligomerization and aggregation of Aβ. Taking into account the similarity in the structural organization of zinc-binding sites within Aβ and angiotensin-converting enzyme (ACE), we hypothesized that inhibitors of the ACE active sites could specifically interact with the 11EVHH14 site of Aβ. Using a surface plasmon resonance biosensor and nuclear magnetic resonance spectroscopy, we have found that the ACE inhibitor enalaprilat effectively inhibits zinc-dependent dimerization of the metal-binding domains of intact Aβ and Aβ with isomerized Asp7 (isoAβ). We have also found that enalaprilat protects SH-SY5Y human neuroblastoma cells from the toxic effects of Aβ(1-42) and isoAβ(1-42), which are among the most common components of amyloid plaques. The results confirm the role of zincdependent oligomerization of Aβ in AD pathogenesis and make it possible one to consider enalaprilat as a prototype of antiaggregation agents for treating AD.

Alzheimer's disease, amyloid-beta, isoaspartate, enalaprilat, zinc, NMR spectroscopy, surface plasmon resonance, neuroblastoma SH-SY5Y