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.

Caitriona M Long-Smith, Sean Manning, PL McClean, Meghan F Coakley, Domhnall J O'Halloran, Christian Holscher, Cora O'Neill

Research output: Contribution to journalArticle

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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 pS(616)), 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 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 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 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 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.
LanguageEnglish
Pages102-14
JournalNeuroMolecular Medicine
Volume15
Issue number1
DOIs
Publication statusPublished - 2013

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Insulin Receptor Substrate Proteins
Insulin Receptor
Amyloid Plaques
Neuroglia
Alzheimer Disease
Pathology
Pharmaceutical Preparations
Glucagon-Like Peptide 1
Neurites
Up-Regulation
Gliosis
Microglia
Frontal Lobe
Liraglutide
Astrocytes
Serine
Type 2 Diabetes Mellitus
Insulin Resistance
Body Weight
Insulin

Cite this

Long-Smith, Caitriona M ; Manning, Sean ; McClean, PL ; Coakley, Meghan F ; O'Halloran, Domhnall J ; Holscher, Christian ; O'Neill, Cora. / 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. In: NeuroMolecular Medicine. 2013 ; Vol. 15, No. 1. pp. 102-14.
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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 pS(616)), 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 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 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 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 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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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. / Long-Smith, Caitriona M; Manning, Sean; McClean, PL; Coakley, Meghan F; O'Halloran, Domhnall J; Holscher, Christian; O'Neill, Cora.

In: NeuroMolecular Medicine, Vol. 15, No. 1, 2013, p. 102-14.

Research output: Contribution to journalArticle

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T1 - 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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