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Antidiabetic Polypill Improves Central Pathology and Cognitive Impairment in a Mixed Model of Alzheimer’s Disease and Type 2 Diabetes

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Abstract

Type 2 diabetes (T2D) is an important risk factor to suffer dementia, being Alzheimer’s disease (AD) as the most common form. Both AD and T2D are closely related to aging and with a growing elderly population it might be of relevance to explore new therapeutic approaches that may slow or prevent central complications associated with metabolic disorders. Therefore, we propose the use of the antidiabetic polypill (PP), a pharmacological cocktail, commonly used by T2D patients that include metformin, aspirin, simvastatin, and an angiotensin-converting enzyme inhibitor. In order to test the effects of PP at the central level, we have long-term treated a new mixed model of AD-T2D, the APP/PS1xdb/db mouse. We have analyzed AD pathological features and the underlying specific characteristics that relate AD and T2D. As expected, metabolic alterations were ameliorated after PP treatment in diabetic mice, supporting a role for PP in maintaining pancreatic activity. At central level, PP reduced T2D-associated brain atrophy, showing both neuronal and synaptic preservation. Tau and amyloid pathologies were also reduced after PP treatment. Furthermore, we observed a reduction of spontaneous central bleeding and inflammation after PP treatment in diabetic mice. As consequence, learning and memory processes were improved after PP treatment in AD, T2D, and AD-T2D mice. Our data provide the basis to further analyze the role of PP, as an alternative or adjuvant, to slow down or delay the central complications associated with T2D and AD.

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Acknowledgements

We thank the animal facility (SEPA) of the University of Cadiz for their support and Consuelo Rivera Sanchez and Miguel Angel Rodriguez Gomez for their technical support (University of Cadiz). We thank Dr. Dominic Walsh (Brigham and Women’s Hospital, Boston, USA) for providing antibodies. MG-A, National Programme for Research Aimed at the Challenges of Society (BFU 2016-75038-R), financed by the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER). Ministerio de Educación, Cultura y Deporte en el marco del Programa Estatal de Promoción del Talento y su Empleabilidad en I + D + i, Subprograma Estatal de Movilidad, del Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (PRX16/00246). Fundación Eugenio Rodríguez Pascual (2015). Proyectos de Excelencia, Consejería de Economía, Innovación, Ciencia y Empleo Junta de Andalucía (P11-CTS-7847). TS-J, European Research Council (ALZSYN), Alzheimer’s Society, Alzheimer’s Research UK and the Scottish Government, UK Demetia Research Institute, and University of Edinburgh Wellcome Trust ISSF. TS-J is a member of the FENS-Kavli Network of Excellence.

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Authors and Affiliations

  1. Division of Physiology, School of Medicine, Instituto de Investigación e Innovación en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Universidad de Cadiz, Plaza Fragela sn, 4 piso 410, Cadiz, Spain

    Carmen Infante-Garcia, Juan Jose Ramos-Rodriguez, Carmen Hierro-Bujalance, Esperanza Ortegon & Monica Garcia-Alloza

  2. UK Dementia Research Institute, Centre for Discovery Brain Sciences, Edinburgh Neuroscience, and Centre for Dementia Prevention, The University of Edinburgh, Edinburgh, UK

    Eleanor Pickett, Rosemary Jackson & Tara Spires-Jones

  3. Clinical Management Unit of Laboratories, Hospital Universitario Puerta del Mar, Cadiz, Spain

    Fernando Hernandez-Pacho

Authors
  1. Carmen Infante-Garcia
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  2. Juan Jose Ramos-Rodriguez
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  3. Carmen Hierro-Bujalance
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  4. Esperanza Ortegon
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  5. Eleanor Pickett
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  6. Rosemary Jackson
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  7. Fernando Hernandez-Pacho
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  8. Tara Spires-Jones
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  9. Monica Garcia-Alloza
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Contributions

CI-G performed the experiments, analyzed the data, and drafted the manuscript; JJR-R, CH-B, RJ, and FH-P performed the experiments and analyzed the data; TSJ analyzed the data, drafted and reviewed the manuscript; MGA conceived the study, analyzed the experiments, and wrote the manuscript approved by all authors.

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Correspondence to Monica Garcia-Alloza.

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Infante-Garcia, C., Ramos-Rodriguez, J.J., Hierro-Bujalance, C. et al. Antidiabetic Polypill Improves Central Pathology and Cognitive Impairment in a Mixed Model of Alzheimer’s Disease and Type 2 Diabetes. Mol Neurobiol 55, 6130–6144 (2018). https://doi.org/10.1007/s12035-017-0825-7

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