Cited by 723Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: Link to brain reductions in acetylcholine

Rivera, Enrique J., Goldin, Alison, Fulmer, Noah, Tavares, Rose, Wands, Jack R., de la Monte, Suzanne M.·2005·Journal of Alzheimer s Disease

DOI 10.3233/jad-2005-8304

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Abstract

Reduced glucose utilization and energy metabolism occur early in the course of Alzheimer's disease (AD) and correlate with impaired cognition. Glucose utilization and energy metabolism are regulated by insulin and insulin-like growth factor I (IGF-I), and correspondingly, studies have shown that cognitive impairment may be improved by glucose or insulin administration. Recently, we demonstrated significantly reduced levels of insulin and IGF-I polypeptide genes and their corresponding receptors in advanced AD relative to aged control brains. The abnormalities in gene expression were accompanied by impaired survival signaling downstream through PI3 kinase-Akt. The present work characterizes the abnormalities in insulin and IGF gene expression and receptor binding in brains with different Braak stage severities of AD. Realtime quantitative RT-PCR analysis of frontal lobe tissue demonstrated that increasing AD Braak Stage was associated with progressively reduced levels of mRNA corresponding to insulin, IGF-I, and IGF-II polypeptides and their receptors, tau, which is regulated by insulin and IGF-I, and the Hu D neuronal RNA binding protein. In contrast, progressively increased levels of amyloid beta protein precursor (AbetaPP), glial fibrillary acidic protein, and the IBA1/AIF1 microglial mRNA transcripts were detected with increasing AD Braak Stage. Impairments in growth factor and growth factor receptor expression and function were associated with increasing AD Braak stage dependent reductions in insulin, IGF-I, and IGF-II receptor binding, ATP levels, and choline acetyltransferase (ChAT) expression. Further studies demonstrated that: 1) ChAT expression increases with insulin or IGF-I stimulation; 2) ChAT is expressed in insulin and IGF-I receptor-positive cortical neurons; and 3) ChAT co-localization in insulin or IGF-I receptor-positive neurons is reduced in AD. Together, these data provide further evidence that AD represents a neuro-endocrine disorder that resembles a unique form of diabetes mellitus (? Type 3) and progresses with severity of neurodegeneration.

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“AD is associated with the reduced level of choline acetyl transferase (ChAT) expression and the insulin resistance is thought to be involved [160].”
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“…impairment, brain insulin/insulin-like growth factor (IGF) resistance neuroinﬂammation, and dysregulated metabolism [18–24] as occur in AD [4, 25–28], yet when delivered systemically, streptozotocin causes diabetes mellitus were ﬁnally interconnected by the realization that streptozotocin is…”
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“Aβ accumulation/immune dysfunction [6, 10, 11, 19-27, 47, 48, 50, 52-54]”
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“In the anterior frontal cortex at Braak stages II and III insulin, insulin receptor, insulin-like growth factor I (IGFI), IGFI receptor and IGFII gene expression are reduced compared to control tissue from Braak stages 0 and I (Rivera et al., 2005).”
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“…de la Monte and collaborators drew attention to the fact that human post-mortem brains from well characterized AD subjects showed molecular and biochemical alterations typical of T2D-related peripheral IR [122], and that could compromise neuronal energy metabolism, plasticity, and survival [123].”
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“Reductions in brain insulin signaling due to insulin deficiency or insulin receptor resistance could account for the majority of molecular, biochemical, and histopathological lesions, as well as cognitive impairment in AD [2,10-18].”
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Insulin-Like Growth Factor Binding Protein 2 Is Associated With Biomarkers of Alzheimer’s Disease Pathology and Shows Differential Expression in Transgenic Mice
Bonham, L. W., Geier, E. G., Steele, N. Z. R., Holland, D., Miller, B. L., Dale, A. M., Desikan, R. S., Yokoyama, J. S., & Initiative, A. D. N. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00476 · Cited by 43
“, IR substrate-1), and decreased IR and IGF receptor (IGFR) expression (Watson and Craft, 2003; Rivera et al., 2005; Steen et al., 2005; Holscher and Li, 2010; de la Monte, 2012; Talbot et al., 2012; Freiherr et al., 2013; Stanley et al., 2016).”
Background

Authors: Rivera, E. J., Goldin, A., Fulmer, N., Tavares, R., Wands, J. R., & de la Monte, S. M.
Affiliations: Brown University (US)
Departments of Pathology and Medicine, Rhode Island Hospital and Brown Medical School, Providence, RI, USA
ORCID: Wands, Jack R.
Venue: Journal of Alzheimer s Disease
Publisher: SAGE Publications
Published: 2005-12-05
Volume: 8
Issue: 3
Pages: 247-268
ISSN: 1387-2877 (ISSN-L)
1875-8908
DOI: 10.3233/jad-2005-8304
OpenAlex: W1718410121
Cited by: 723
References: 71
Citations by year: 2026: 16 · 2025: 24 · 2024: 32 · 2023: 35 · 2022: 56 · 2021: 45 · 2020: 43 · 2019: 52 · 2018: 46 · 2017: 29 · 2016: 43 · 2015: 44 · 2014: 51 · 2013: 42 · 2012: 43
FWCI: 8.79
Type: journal article
Language: en
Open access: closed
Locations: Journal of Alzheimer s Disease (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute on Alcohol Abuse and Alcoholism (AA12458, AA-02666, AA11931)
National Institute on Aging (P50 AG05128, P50AG005128)
National Center for Research Resources (P20RR 15578, P20RR015578)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: Alzheimer's disease, insulin
MeSH terms: Acetylcholine, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Apolipoproteins E, Brain, Choline O-Acetyltransferase, Cognition Disorders, Female, Genotype, Glucose, Humans, Insulin, Insulin Resistance, Insulin-Like Growth Factor I, Male, RNA, Messenger, Gene Expression, Amyloid beta-Protein Precursor, tau Proteins, DNA Primers, Disease Progression, Reverse Transcriptase Polymerase Chain Reaction

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Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: Link to brain reductions in acetylcholine

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