The Y-Box Binding Protein 1 Suppresses Alzheimer's Disease Progression in Two Animal Models

N V Bobkova; D N Lyabin; N I Medvinskaya; A N Samokhin; P V Nekrasov; I V Nesterova; I Y Aleksandrova; O G Tatarnikova; A G Bobylev; I M Vikhlyantsev; M S Kukharsky; A A Ustyugov; D N Polyakov; I A Eliseeva; D A Kretov; S G Guryanov; L P Ovchinnikov

doi:10.1371/journal.pone.0138867

The Y-Box Binding Protein 1 Suppresses Alzheimer's Disease Progression in Two Animal Models

PLoS One. 2015 Sep 22;10(9):e0138867. doi: 10.1371/journal.pone.0138867. eCollection 2015.

Authors

N V Bobkova¹, D N Lyabin², N I Medvinskaya¹, A N Samokhin¹, P V Nekrasov¹, I V Nesterova¹, I Y Aleksandrova¹, O G Tatarnikova¹, A G Bobylev³, I M Vikhlyantsev³, M S Kukharsky⁴, A A Ustyugov⁴, D N Polyakov², I A Eliseeva², D A Kretov², S G Guryanov², L P Ovchinnikov²

Affiliations

¹ Institute of Cell Biophysics, RAS, Pushchino, Moscow Region, Russia.
² Institute of Protein Research, RAS, Pushchino, Moscow Region, Russia.
³ Institute of Theoretical and Experimental Biophysics, RAS, Pushchino, Moscow Region, Russia.
⁴ Institute of Physiologically Active Compounds, RAS, Chernogolovka, Moscow Region, Russia.

Abstract

The Y-box binding protein 1 (YB-1) is a member of the family of DNA- and RNA binding proteins. It is involved in a wide variety of DNA/RNA-dependent events including cell proliferation and differentiation, stress response, and malignant cell transformation. Previously, YB-1 was detected in neurons of the neocortex and hippocampus, but its precise role in the brain remains undefined. Here we show that subchronic intranasal injections of recombinant YB-1, as well as its fragment YB-11-219, suppress impairment of spatial memory in olfactory bulbectomized (OBX) mice with Alzheimer's type degeneration and improve learning in transgenic 5XFAD mice used as a model of cerebral amyloidosis. YB-1-treated OBX and 5XFAD mice showed a decreased level of brain β-amyloid. In OBX animals, an improved morphological state of neurons was revealed in the neocortex and hippocampus; in 5XFAD mice, a delay in amyloid plaque progression was observed. Intranasally administered YB-1 penetrated into the brain and could enter neurons. In vitro co-incubation of YB-1 with monomeric β-amyloid (1-42) inhibited formation of β-amyloid fibrils, as confirmed by electron microscopy. This suggests that YB-1 interaction with β-amyloid prevents formation of filaments that are responsible for neurotoxicity and neuronal death. Our data are the first evidence for a potential therapeutic benefit of YB-1 for treatment of Alzheimer's disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / genetics
Alzheimer Disease / physiopathology
Alzheimer Disease / prevention & control*
Amyloid beta-Peptides / metabolism
Amyloid beta-Peptides / pharmacology
Animals
Animals, Newborn
Brain / drug effects
Brain / metabolism
Brain / pathology
Cells, Cultured
Disease Models, Animal
Disease Progression
Electrophoresis, Polyacrylamide Gel
Humans
Immunohistochemistry
Male
Maze Learning / drug effects
Mice, Inbred C57BL
Mice, Inbred Strains
Mice, Transgenic
Microscopy, Confocal
Neurons / drug effects
Neurons / metabolism
Olfactory Bulb / surgery
Peptide Fragments / pharmacology*
Plaque, Amyloid / metabolism
Plaque, Amyloid / prevention & control
Rats
Recombinant Proteins / pharmacology*
Y-Box-Binding Protein 1 / chemistry
Y-Box-Binding Protein 1 / genetics
Y-Box-Binding Protein 1 / pharmacology*

Substances

Amyloid beta-Peptides
Peptide Fragments
Recombinant Proteins
Y-Box-Binding Protein 1
amyloid beta-protein (1-42)

Grants and funding

This study was supported by the Russian Scientific Foundation (http://www.rscf.ru) (#14-14-00879 - molecular and cellular mechanisms of YB-1 involvement in Alzheimer’s disease (AD) genesis and YB-1 preparation for in vivo and in vitro experiments; #14-23-00160 – transgenic mice production) and by the Russian Foundation for Basic Research (http://www.rfbr.ru) (# 13-04-00881 - behavioral effects of YB-1 and its fragments on olfactory bulbectomized mice used as a model of sporadic AD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.