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 ß-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 ß-amyloid (1-42) inhibited formation of ß-amyloid fibrils, as confirmed by electron microscopy. This suggests that YB-1 interaction with ß-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.
Subject(s)
Alzheimer Disease/prevention & control , Peptide Fragments/pharmacology , Recombinant Proteins/pharmacology , Y-Box-Binding Protein 1/pharmacology , Alzheimer Disease/genetics , Alzheimer Disease/physiopathology , 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 , Plaque, Amyloid/metabolism , Plaque, Amyloid/prevention & control , Rats , Y-Box-Binding Protein 1/chemistry , Y-Box-Binding Protein 1/geneticsABSTRACT
Epidemiological studies demonstrated association between head injury (HI) and the subsequent development of Alzheimer's disease (AD). Certain hallmarks of AD, e.g. amyloid-ß (Aß) containing deposits, may be found in patients following traumatic BI (TBI). Recent studies uncover the cellular prion protein, PrP(C), as a receptor for soluble polymeric forms of Aß (sAß) which are an intermediate of such deposits. We aimed to test the hypothesis that targeting of PrP(C) can prevent Aß related spatial memory deficits in olfactory bulbectomized (OBX) mice utilized here to resemble some clinical features of AD, such as increased level of Aß, memory loss and deficit of the CNS cholin- and serotonin-ergic systems. We demonstrated that immunization with the a.a. 95-123 fragment of cellular prion (PrP-I) recovered cortical and hippocampus neurons from OBX induced degeneration, rescued spatial memory loss in Morris water maze test and significantly decrease the Aß level in brain tissue of these animals. Affinity purified anti-PrP-I antibodies rescued pre-synaptic biomarker synaptophysin eliciting similar effect on memory of OBX mice, and protected hippocampal neurones from Aß25-35-induced toxicity in vitro. Immunization OBX mice with a.a. 200-213 fragment of cellular prion (PrP-II) did not reach a significance in memory protection albeit having similar to PrP-I immunization impact on Aß level in brain tissue. The observed positive effect of targeting the PrP-I by either active or passive immunization on memory of OBX mice revealed the involvement of the PrP(C) in AD-like pathology induced by olfactory bulbectomy. This OBX model may be a useful tool for mechanistic and preclinical therapeutic investigations into the association between PrP(C) and AD.
Subject(s)
Memory Disorders/therapy , Nerve Degeneration/therapy , Neuroprotective Agents/immunology , Peptide Fragments/immunology , PrPC Proteins/immunology , Prions/immunology , Amyloid beta-Peptides/metabolism , Animals , Antibodies/immunology , Hippocampus/pathology , Immunization , Immunization, Passive , Male , Maze Learning/physiology , Mice , Mice, Inbred Strains , Neurons/pathology , Olfactory Bulb/pathology , Rats , Rats, Sprague-Dawley , Temporal Lobe/pathologyABSTRACT
Studies of imidazole-4,5- and pyrazole-3,4-dicarboxylic acid derivatives revealed a number of new agonists and antagonists of N-methyl-D-aspartic acid (NMDA) receptors. Studies were based on whole-cell patch-clamp methods applied to rat hippocampus pyramidal cells. Increases in the lipophilicity of the environment of the nitrogen atom, keeping the distance between the terminal acid functions constant, led to a weakening of NMDA antagonism and increases in NMDA antagonism. Increases in the lipophilicity around the nitrogen atom could also lead to less of selectivity in the interaction with NMDA receptors and the appearance of non-NMDA antagonist properties.
