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The Diabetes Drug Liraglutide Ameliorates Aberrant Insulin Receptor Localisation and Signalling in Parallel with Decreasing Both Amyloid-β Plaque and Glial Pathology in a Mouse Model of Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) has been shown to involve desensitised insulin receptor (IR) signalling. Liraglutide, a novel glucagon-like peptide 1 (GLP-1) analogue that facilitates insulin signalling, is currently approved for use in type 2 diabetes mellitus. In the present study, we show that distinctive alterations in the localisation and distribution of the IR and increased levels of insulin receptor substrate (IRS)-1 phosphorylated at serine 616 (IRS-1 pS616), a key marker of insulin resistance, are associated with amyloid-β plaque pathology in the frontal cortex of a mouse model of AD, APPSWE/PS1dE9. Altered IR status in APPSWE/PS1dE9 is most evident in extracellular deposits with the appearance of dystrophic neurites, with significantly increased IRS-1 pS616 levels detected within neurons and neurites. The IR and IRS-1 pS616 changes occur in the vicinity of all plaques in the APPSWE/PS1dE9 brain, and a significant upregulation of astrocytes and microglia surround this pathology. We show that liraglutide treatment for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old mice significantly decreases IR aberrations in conjunction with a concomitant decrease in amyloid plaque load and levels of IRS-1 pS616. Liraglutide also induces a highly significant reduction in astrocytosis and microglial number associated with both plaques and IR pathology. The amelioration of IR aberrations and attenuation of IRS-1 pS616 upregulation, plaque and glial activation in APPSWE/PS1dE9 mice treated with liraglutide support the investigation of the therapeutic potential of liraglutide and long-lasting GLP-1 agonists in patients with AD.

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Acknowledgments

Financial support was provided by The Health Research Board of Ireland, Science Foundation Ireland (Research Frontiers Programme), Sanofi-Aventis and the Alzheimer’s Society (UK).

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Authors and Affiliations

  1. Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland

    Caitriona M. Long-Smith, Sean Manning, Meghan F. Coakley & Cora O’Neill

  2. School of Biomedical Sciences, Ulster University, Coleraine, BT52 1SA, Northern Ireland, UK

    Paula L. McClean & Christian Holscher

  3. Department of Endocrinology and Metabolism, Cork University Hospital, Wilton, Cork, Ireland

    Domhnall J. O’Halloran

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  1. Caitriona M. Long-Smith
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  2. Sean Manning
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Correspondence to Cora O’Neill.

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Caitriona M. Long-Smith and Sean Manning equally contributed to this manuscript.

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Long-Smith, C.M., Manning, S., McClean, P.L. et al. The Diabetes Drug Liraglutide Ameliorates Aberrant Insulin Receptor Localisation and Signalling in Parallel with Decreasing Both Amyloid-β Plaque and Glial Pathology in a Mouse Model of Alzheimer’s Disease. Neuromol Med 15, 102–114 (2013). https://doi.org/10.1007/s12017-012-8199-5

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