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Glycogen phosphorylase inhibition improves cognitive function of aged mice
Authors:Dominika Drulis-Fajdasz  Adam Krzystyniak  Alicja Puścian  Agata Pytyś  Kinga Gostomska-Pampuch  Natalia Pudełko-Malik  Jerzy Ł. Wiśniewski  Piotr Młynarz  Arkadiusz Miazek  Tomasz Wójtowicz  Jakub Włodarczyk  Kamila Duś-Szachniewicz  Agnieszka Gizak  Jacek R. Wiśniewski  Dariusz Rakus
Affiliation:1. Department of Molecular Physiology and Neurobiology, University of Wroclaw, Wroclaw, Poland;2. Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland;3. Nencki-EMBL Partnership for Neural Plasticity and Brain Disorders – BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland;4. Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Wroclaw, Poland

Biochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany;5. Department of Biochemistry, Molecular Biology and Biotechnology, Faculty of Chemistry, Wroclaw University of Science and Technology, Wroclaw, Poland;6. Laboratory of Tumor Immunology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland;7. Department of Clinical and Experimental Pathology, Institute of General and Experimental Pathology, Wroclaw Medical University, Wroclaw, Poland;8. Biochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany

Abstract:Inhibition of glycogen breakdown blocks memory formation in young animals, but it stimulates the maintenance of the long-term potentiation, a cellular mechanism of memory formation, in hippocampal slices of old animals. Here, we report that a 2-week treatment with glycogen phosphorylase inhibitor BAY U6751 alleviated memory deficits and stimulated neuroplasticity in old mice. Using the 2-Novel Object Recognition and Novel Object Location tests, we discovered that the prolonged intraperitoneal administration of BAY U6751 improved memory formation in old mice. This was accompanied by changes in morphology of dendritic spines in hippocampal neurons, and by “rejuvenation” of hippocampal proteome. In contrast, in young animals, inhibition of glycogen degradation impaired memory formation; however, as in old mice, it did not alter significantly the morphology and density of cortical dendritic spines. Our findings provide evidence that prolonged inhibition of glycogen phosphorolysis improves memory formation of old animals. This could lead to the development of new strategies for treatment of age-related memory deficits.
Keywords:aging  behavioral tests  glycogen phosphorylase (Pyg)  hippocampus  memory formation/deficits
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