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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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, Paula L. et al.
In: NeuroMolecular Medicine, Vol. 15, No. 1, 03.2013, p. 102-114.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

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@article{7cd7ca28643442b2b1cb761461bbe8e1,

title = "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",

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.",

keywords = "Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Astrocytes, Disease Models, Animal, Female, Frontal Lobe, Glucagon-Like Peptide 1, Hypoglycemic Agents, Insulin Receptor Substrate Proteins, Insulin Resistance, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia, Mutation, Missense, Neuroprotective Agents, Phosphorylation, Plaque, Amyloid, Presenilin-1, Protein Processing, Post-Translational, Protein Transport, Receptor, Insulin, Signal Transduction",

author = "Long-Smith, {Caitriona M.} and Sean Manning and McClean, {Paula L.} and Coakley, {Meghan F.} and O'Halloran, {Domhnall J.} and Christian Holscher and Cora O'Neill",

year = "2013",

month = mar,

doi = "10.1007/s12017-012-8199-5",

language = "English",

volume = "15",

pages = "102--114",

journal = "NeuroMolecular Medicine",

issn = "1559-1174",

publisher = "Humana Press",

number = "1",

}

RIS

TY - JOUR

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

AU - Long-Smith, Caitriona M.

AU - Manning, Sean

AU - McClean, Paula L.

AU - Coakley, Meghan F.

AU - O'Halloran, Domhnall J.

AU - Holscher, Christian

AU - O'Neill, Cora

PY - 2013/3

Y1 - 2013/3

N2 - 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.

AB - 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.

KW - Alzheimer Disease

KW - Amyloid beta-Peptides

KW - Amyloid beta-Protein Precursor

KW - Animals

KW - Astrocytes

KW - Disease Models, Animal

KW - Female

KW - Frontal Lobe

KW - Glucagon-Like Peptide 1

KW - Hypoglycemic Agents

KW - Insulin Receptor Substrate Proteins

KW - Insulin Resistance

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Microglia

KW - Mutation, Missense

KW - Neuroprotective Agents

KW - Phosphorylation

KW - Plaque, Amyloid

KW - Presenilin-1

KW - Protein Processing, Post-Translational

KW - Protein Transport

KW - Receptor, Insulin

KW - Signal Transduction

U2 - 10.1007/s12017-012-8199-5

DO - 10.1007/s12017-012-8199-5

M3 - Journal article

C2 - 23011726

VL - 15

SP - 102

EP - 114

JO - NeuroMolecular Medicine

JF - NeuroMolecular Medicine

SN - 1559-1174

IS - 1

ER -

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