Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling

Moloney, Aileen M.; Griffin, Rebecca J.; Timmons, Suzanne; O’Connor, Rosemary; Ravid, Rivka; O’Neill, Cora

doi:10.1016/j.neurobiolaging.2008.04.002

Cited by 764Alzheimer's disease research and treatmentsGrowth Hormone and Insulin-like Growth FactorsDementia and Cognitive Impairment Research

Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling

Moloney, Aileen M., Griffin, Rebecca J., Timmons, Suzanne, O’Connor, Rosemary, Ravid, Rivka, O’Neill, Cora·2010·Neurobiology of Aging

DOI 10.1016/j.neurobiolaging.2008.04.002

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Abstract

Insulin like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) signalling control vital growth, survival and metabolic functions in the brain. Here we describe specific and significant alterations in IGF-1R, IR, and their key substrate adaptor proteins IRS-1 and IRS-2 in Alzheimer's disease (AD). Western immunoblot analysis detected increased IGF-1R levels, and decreased levels of IGF-1-binding protein-2 (IGFBP-2), a major IGF-1-binding protein, in AD temporal cortex. Increased IGF-1R was observed surrounding and within amyloid-beta (Abeta)-containing plaques, also evident in an animal model of AD, and in astrocytes in AD. However, despite the overall increase in IGF-1R levels, a significantly lower number of neurons expressed IGF-1R in AD, and IGF-1R was aberrantly distributed in AD neurons especially evident in those with neurofibrillary tangles (NFTs). IR protein levels were similar in AD and control cases, however, the IR was concentrated intracellularly in AD neurons, unlike its distribution throughout the neuronal cell soma and in dendrites in control brain. Significant decreases in IRS-1 and IRS-2 levels were identified in AD neurons, in association with increased levels of inactivated phospho(Ser312)IRS-1 and phospho(Ser616)IRS-1, where increased levels of these phosphoserine epitopes colocalised strongly with NFTs. Our results show that IGF-1R and IR signalling is compromised in AD neurons and suggest that neurons that degenerate in AD may be resistant to IGF-1R/IR signalling.

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Removal of insulin receptors from the surface of neurons has been verified in Alzheimer's disease brains.
“Removal of IRs from the surface of neurons was subsequently verified in AD brains (Moloney et al., 2010), establishing the pathophysiological significance of the initial cell-based findings.”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Moloney et al., 2010
These receptor pathologies discovered in cell culture have been confirmed in transgenic mouse models and human Alzheimer's disease brain.
“These receptor pathologies discovered in cell culture have been confirmed in tg-mouse models and human AD brain (Cisse et al., 2011; Moloney et al., 2010).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Moloney et al., 2010

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Authors: Moloney, A. M., Griffin, R. J., Timmons, S., O’Connor, R., Ravid, R., & O’Neill, C.
Affiliations: University College Cork (IE)
Netherlands Brain Bank (NL)
ORCID: Timmons, Suzanne
O’Connor, Rosemary
O’Neill, Cora
Venue: Neurobiology of Aging
Publisher: Elsevier BV
Published: 2010-02
Volume: 31
Issue: 2
Pages: 224-243
ISSN: 0197-4580 (ISSN-L)
DOI: 10.1016/j.neurobiolaging.2008.04.002
OpenAlex: W1972609075
Cited by: 764
References: 64
Citations by year: 2026: 15 · 2025: 36 · 2024: 38 · 2023: 50 · 2022: 52 · 2021: 60 · 2020: 66 · 2019: 53 · 2018: 51 · 2017: 47 · 2016: 51 · 2015: 53 · 2014: 55 · 2013: 35 · 2012: 48
FWCI: 11.99
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Neurobiology of Aging (publishedVersion)
PubMed (publishedVersion)
KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Funders: Health Research Board
Science Foundation Ireland (02/IN.1/B070, 05/IN3/B763)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: Alzheimer's disease, IGF-1 receptor, insulin receptor, IRS-1, insulin receptor substrate 2, IGF-1 signaling, insulin signaling, amyloid plaques, neurofibrillary tangles, astrocytes, temporal cortex, receptor subcellular distribution
MeSH terms: Aged, Aged, 80 and over, Alzheimer Disease, Animals, Astrocytes, Female, Humans, Male, Mice, Transgenic, Middle Aged, Neurons, Receptor, Insulin, Temporal Lobe, Signal Transduction, Neurofibrillary Tangles, Receptor, IGF Type 1, Phosphatidylinositol 3-Kinases, Mice, Insulin Receptor Substrate Proteins, Plaque, Amyloid

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Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling

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