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Early Preclinical Changes in Hippocampal CREB-Binding Protein Expression in a Mouse Model of Familial Alzheimer’s Disease

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Abstract

The molecular basis of memory loss in Alzheimer’s disease (AD), the main cause of senile dementia, is under investigation. In the present study, we have focused on the early hippocampal memory-related changes in APPswe/PS1dE9 (APP/PS1) mice, a well-established mouse model of familial AD. It is well known that molecules like cAMP response element binding (CREB) and binding protein (CBP) play a crucial role in memory consolidation. We analyzed CBP on its transcriptional activity and protein levels, finding a significant downregulation of both of them at 3-month-old mice. In addition, the downregulation of this molecule was associated with a decrease on acetylation levels of histone H3 in the hippocampus of APP/PS1 mice. Moreover, the p-CREB levels, which are important for memory acquisition at 3 months in APP/PS1 mice, were downregulated. Furthermore, we suggest that early neuroinflammation, especially due to the Tnfα gene increased expression, could also be responsible to this process of memory loss. Given all the previously mentioned results, we propose that an early suitable treatment to prevent the evolution of the disease should include a combination of drugs, including anti-inflammatories, which may decrease glial activation and Tnfα levels, and phosphodiesterase inhibitors that increase cAMP levels.

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Acknowledgements

This work was supported by the Spanish Ministry of Science and Innovation SAF-2016-33307, PI2016/01, CB06/05/0024 (CIBERNED) and the European Regional Development Funds. Research team from UB and URV belongs to 2014SGR-525 from Generalitat de Catalunya.

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Authors and Affiliations

  1. Departament de Farmacología, Toxicología I Química Terapéutica, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Barcelona, Spain

    Miren Ettcheto, Sonia Abad, Dmitry Petrov, Oriol Busquets, Merce Pallàs & Antoni Camins

  2. Departament de Bioquímica, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Spain

    Miren Ettcheto, Ignacio Pedrós, Oriol Busquets & Jaume Folch

  3. Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain

    Miren Ettcheto, Sonia Abad, Dmitry Petrov, Ignacio Pedrós, Oriol Busquets, Eva Carro, Carme Auladell, Merce Pallàs, Jaume Folch & Antoni Camins

  4. Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain

    Miren Ettcheto, Oriol Busquets, Carme Auladell, Merce Pallàs & Antoni Camins

  5. Unitat de Farmacia, Tecnologia Farmacèutica i Fisico-química, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain

    Elena Sánchez-López

  6. Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain

    Elena Sánchez-López

  7. Department of Biological Sciences, Kent State University, Kent, OH, USA

    Gemma Casadesús

  8. Departamento de Biología Celular y Molecular, Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, CUCBA, Mexico

    Carlos Beas-Zarate

  9. Neuroscience Group, Instituto de Investigacion Hospital 12 de Octubre, Madrid, Spain

    Eva Carro

  10. Departament de Biologia Cel•lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain

    Carme Auladell

  11. Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile

    Jordi Olloquequi

  12. Unitat de Farmacologia i Farmacognosia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Barcelona, Spain. Av. Joan XXIII s/n, E-08028, Barcelona, Spain

    Antoni Camins

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  1. Miren Ettcheto
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  2. Sonia Abad
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  14. Antoni Camins
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Correspondence to Antoni Camins.

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Jaume Folch and Antoni Camins are senior co-authors

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Ettcheto, M., Abad, S., Petrov, D. et al. Early Preclinical Changes in Hippocampal CREB-Binding Protein Expression in a Mouse Model of Familial Alzheimer’s Disease. Mol Neurobiol 55, 4885–4895 (2018). https://doi.org/10.1007/s12035-017-0690-4

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