Journal
NEUROMOLECULAR MEDICINE
Volume 15, Issue 1, Pages 102-114Publisher
HUMANA PRESS INC
DOI: 10.1007/s12017-012-8199-5
Keywords
Alzheimer's disease; Diabetes; GLP-1; Liraglutide; Insulin receptor; Inflammation
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Funding
- Health Research Board of Ireland
- Science Foundation Ireland (Research Frontiers Programme)
- Sanofi-Aventis
- Alzheimer's Society (UK)
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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 pS(616)), a key marker of insulin resistance, are associated with amyloid-beta plaque pathology in the frontal cortex of a mouse model of AD, APP(SWE)/PS1dE9. Altered IR status in APP(SWE)/PS1dE9 is most evident in extracellular deposits with the appearance of dystrophic neurites, with significantly increased IRS-1 pS(616) levels detected within neurons and neurites. The IR and IRS-1 pS(616) changes occur in the vicinity of all plaques in the APP(SWE)/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 pS(616). 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 pS(616) upregulation, plaque and glial activation in APP(SWE)/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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