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

Y-Box 结合蛋白 1 抑制两种动物模型中的阿尔茨海默病进展

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作者: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

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.

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