Brain insulin resistance triggers early onset Alzheimer disease in Down syndrome

Tramutola, Antonella; Lanzillotta, Chiara; Di Domenico, Fabio; Head, Elizabeth; Butterfield, D. Allan; Perluigi, Marzia; Barone, Eugenio

doi:10.1016/j.nbd.2020.104772

Cited by 73Down syndrome and intellectual disability researchAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Brain insulin resistance triggers early onset Alzheimer disease in Down syndrome

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Tramutola, Antonella, Lanzillotta, Chiara, Di Domenico, Fabio, Head, Elizabeth, Butterfield, D. Allan, Perluigi, Marzia, Barone, Eugenio·2020·Neurobiology of Disease

DOI 10.1016/j.nbd.2020.104772

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Abstract

Dysregulation of insulin signaling pathway with reduced downstream neuronal survival and plasticity mechanisms is a fundamental abnormality observed in Alzheimer's disease (AD) brain. This phenomenon, known as brain insulin resistance, is associated with poor cognitive performance and is driven by the uncoupling of insulin receptor (IR) from its direct substrate (IRS1). Considering that Down syndrome (DS) and AD neuropathology share many common features, we investigated metabolic aspects of neurodegeneration, i.e., brain insulin resistance, in DS and whether it would contribute to early onset AD in DS population. Changes of levels and activation of main brain proteins belonging to the insulin signaling pathway (i.e., IR, IRS1, PTEN, GSK3β, PKCζ, AS160, GLUT4) were evaluated. Furthermore, we analyzed whether changes of these proteins were associated with alterations of: (i) proteins regulating brain energy metabolism; (ii) APP cleavage; and (ii) regulation of synaptic plasticity mechanisms in post-mortem brain samples collected from people with DS before and after the development of AD pathology (DSAD) compared with their age-matched controls. We found that DS cases were characterized by key markers of brain insulin resistance (reduced IR and increased IRS1 inhibition) early in life. Furthermore, downstream from IRS1, an overall uncoupling among the proteins of insulin signaling was observed. Dysregulated brain insulin signaling was associated with reduced hexokinase II (HKII) levels and proteins associated with mitochondrial complexes levels as well as with reduced levels of syntaxin in DS cases. Tellingly, these alterations precede the development of AD neuropathology and clinical presentations in DS. We propose that markers of brain insulin resistance rise earlier with age in DS compared with the general population and may contribute to the cognitive impairment associated with the early development of AD in DS.

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These multi-omics analyses provide an initial account of aberrant mTOR/INS signaling that may contribute to AD-related pathology in individuals with DS.
“These multi‐omics analyses provide an initial account of aberrant mTOR/INS signaling that may contribute to AD‐related pathology in individuals with DS. 42 , 60”
From Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations (2026) · cites this paper as [42]
The Discussion (page not provided) links altered insulin signaling in Down syndrome to AD neuropathological hallmarks and discusses increased mTOR activation in the same autopsy cases. But the paper describes targeted protein analyses, not multi-omics analyses; its mTOR finding is reported from earlier work rather than measured in the current study. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Reduced insulin/PI3K signaling contributes to widespread proteomic synaptic and metabolic compromise in CA1/CA2, even when transcriptional changes in PI3K components are modest.
“Although CA1 and CA2 did not show the largest changes in PIK3CA transcriptionally, each exhibited pronounced proteomic evidence of downstream pathway remodeling, suggesting that reduced insulin/PI3K signaling contributes to widespread proteomic synaptic and metabolic compromise in CA1/CA2, 42 , 66 , 67 even when transcriptional changes in PI3K components are modest.”
From Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations (2026) · cites this paper as [42]
The Discussion links impaired brain insulin signaling to altered synaptic-plasticity proteins and reduced energy metabolism. It does not establish proteomic changes in CA1/CA2 or compare them with PI3K-component transcription; it also reports hyperactivation, rather than reduced activation, of the PI3K/Akt axis in the Down syndrome cases studied. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
PTEN is a key negative regulator within the shared PI3K/Akt signaling cascade.
“PTEN is a key negative regulator within the shared PI3K/Akt signaling cascade 42”
From Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations (2026) · cites this paper as [42]

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Erratum: Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy
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Biliverdin Reductase-A Mediates the Beneficial Effects of Intranasal Insulin in Alzheimer Disease
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Spectroscopic Studies of GSK3β Phosphorylation of the Neuronal Tau Protein and Its Interaction with the N-Terminal Domain of Apolipoprotein E
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PTEN: Local and Global Modulation of Neuronal Function in Health and Disease
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Is it possible to improve neurodevelopmental abnormalities in Down syndrome?
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Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome
Domenico, F. D., Tramutola, A., Barone, E., Lanzillotta, C., Defever, O., Arena, A., Zuliani, I., Foppoli, C., Iavarone, F., Vincenzoni, F., et al. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101162 · Cited by 69 · see citing works
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Interleukin-7 mediates glucose utilization in lymphocytes through transcriptional regulation of the hexokinase II gene
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The genetics of PKMζ and memory maintenance
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Molecular Features of Phosphatase and Tensin Homolog (PTEN) Regulation by C-terminal Phosphorylation
Chen, Z., Dempsey, D. R., Thomas, S. N., Hayward, D., Bolduc, D. M., & Cole, P. A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.728980 · Cited by 57 · see citing works
Loss of biliverdin reductase-A favors Tau hyper-phosphorylation in Alzheimer's disease
Sharma, N. K., Tramutola, A., Lanzillotta, C., Arena, A., Blarzino, C., Cassano, T., Butterfield, D. A., Domenico, F. D., Marzia Perluigi, A., & Barone, E. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.02.003 · Cited by 57 · see citing works
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The effect of diabetes and insulin invivo and invitro on a low Km form of hexokinase from various rat tissues
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Biliverdin reductase-A impairment links brain insulin resistance with increased Aβ production in an animal model of aging: Implications for Alzheimer disease
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Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology
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Some morphometric observations on the brains of patients with Down's syndrome: their relationship to age and dementia
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Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain
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Enhanced Dendritic Inhibition and Impaired NMDAR Activation in a Mouse Model of Down Syndrome
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Parallel Compensatory and Pathological Events Associated with Tau Pathology in Middle Aged Individuals with Down Syndrome
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PIP3 but not PIP2 increases GLUT4 surface expression and glucose metabolism mediated by AKT/PKCζ/λ phosphorylation in 3T3L1 adipocytes
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From altered synaptic plasticity to atypical learning: A computational model of Down syndrome
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GSK3β 5'-flanking DNA Methylation and Expression in Alzheimer’s Disease Patients
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Neuroanatomical alterations and synaptic plasticity impairment in the perirhinal cortex of the Ts65Dn mouse model of Down syndrome
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Multiple signalling pathways mediate insulin-stimulated gene expression in 3T3-L1 adipocytes
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GSK3β Modulates Timing-Dependent Long-Term Depression Through Direct Phosphorylation of Kv4.2 Channels
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The Interplay Among Oxidative Stress, Brain Insulin Resistance and AMPK Dysfunction Contribute to Neurodegeneration in Type 2 Diabetes and Alzheimer Disease
Barone, E., Domenico, F. D., Perluigi, M., & Butterfield, D. (2021) · Free Radical Biology & Medicine · doi:10.1016/j.freeradbiomed.2021.09.006 · Cited by 155 · see citing works
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Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review
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Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions
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Proteomics Study of Peripheral Blood Mononuclear Cells in Down Syndrome Children
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Targeting Alzheimer’s Disease: The Critical Crosstalk between the Liver and Brain
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Effects of ketogenic diet on cognitive function of patients with Alzheimer's disease: a systematic review and meta-analysis
Rong, L., Peng, Y., Shen, Q., Chen, K., Fang, B., & Li, W. (2024) · The journal of nutrition health & aging · doi:10.1016/j.jnha.2024.100306 · Cited by 52 · see citing works
Insulin resistance and bioenergetic manifestations: Targets and approaches in Alzheimer's disease
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Insulin resistance, oxidative stress and mitochondrial defects in Ts65dn mice brain: a harmful synergistic path in down syndrome
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The role of insulin/IGF1 signalling in neurodevelopmental and neuropsychiatric disorders – Evidence from human neuronal cell models
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Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3×Tg-AD mice
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Lower GLUT1 and unchanged MCT1 in Alzheimer’s disease cerebrovasculature
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Antioxidants in Down Syndrome: From Preclinical Studies to Clinical Trials
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Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal‐derived extracellular vesicles
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Cellular senescence and premature aging in Down Syndrome
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Developmental Neuropathology and Neurodegeneration of Down Syndrome: Current Knowledge in Humans
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The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome
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Recent Advances on the Analysis and Biological Functions of Cinnamaldehyde and Its Derivatives
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Signalling Pathways Implicated in Alzheimer′s Disease Neurodegeneration in Individuals with and without Down Syndrome
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Redox imbalance and metabolic defects in the context of Alzheimer disease
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Reduced synaptic proteins and SNARE complexes in Down syndrome with Alzheimer's disease and the Dp16 mouse Down syndrome model: Impact of APP gene dose
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Down’s syndrome and COVID-19: risk or protection factor against infection? A molecular and genetic approach
Altable, M., & de la Serna, J. M. (2020) · Neurological Sciences · doi:10.1007/s10072-020-04880-x · Cited by 19 · see citing works
Cinnamaldehyde Regulates Insulin and Caspase-3 Signaling Pathways in the Sporadic Alzheimer’s Disease Model: Involvement of Hippocampal Function via IRS-1, Akt, and GSK-3β Phosphorylation
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Cellular Stress Response (Hormesis) in Response to Bioactive Nutraceuticals with Relevance to Alzheimer Disease
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Exploring the Role of Hsp60 in Alzheimer’s Disease and Type 2 Diabetes: Suggestion for Common Drug Targeting
Zimbone, S., Rosa, M. C. D., Chiechio, S., & Giuffrida, M. L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512456 · Cited by 18 · see citing works
Shaping down syndrome brain cognitive and molecular changes due to aging using adult animals from the Ts66Yah murine model
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Adiponectin Modulation by Genotype and Maternal Choline Supplementation in a Mouse Model of Down Syndrome and Alzheimer’s Disease
Alldred, M. J., Lee, S. H., & Ginsberg, S. D. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10132994 · Cited by 17 · see citing works
GLUT-1 changes in paediatric Huntington disease brain cortex and fibroblasts: an observational case-control study
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Review of Associations of Diabetes and Insulin Resistance With Brain Health in Three Harmonised Cohort Studies of Ageing and Dementia
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The Unraveling
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Role of Biliverdin Reductase A in the Regulation of Insulin Signaling in Metabolic and Neurodegenerative Diseases: An Update
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Catechins as a Potential Dietary Supplementation in Prevention of Comorbidities Linked with Down Syndrome
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From neurodevelopment to neurodegeneration: utilizing human stem cell models to gain insight into Down syndrome
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Chronically Increased Levels of Circulating Insulin Secondary to Insulin Resistance: A Silent Killer
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Altered mitochondrial unfolded protein response and protein quality control promote oxidative distress in down syndrome brain
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Building the Future Therapies for Down Syndrome: The Third International Conference of the T21 Research Society
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Enhancing protein O-GlcNAcylation in down syndrome mice mitigates memory dysfunctions through the rescue of mitochondrial bioenergetics, stress responses and pathological markers
Lanzillotta, C., Prestia, F., Greco, V., Iavarone, F., Cordella, F., Sette, C., Forte, E., Tramutola, A., Lanzillotta, S., Cassano, T., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103769 · Cited by 10 · see citing works
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Stereoscopic Depth Perception and Visuospatial Dysfunction in Alzheimer’s Disease
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Brain insulin resistance in Down syndrome: Involvement of PI3K-Akt/mTOR axis in early-onset of Alzheimer's disease and its potential as a therapeutic target
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Dexamethasone ameliorates Alzheimer’s pathological condition via inhibiting Nf-κB and mTOR signaling pathways
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Integrative Analysis Extracts a Core ceRNA Network of the Fetal Hippocampus With Down Syndrome
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Dynamic Changes of BVRA Protein Levels Occur in Response to Insulin: A Pilot Study in Humans
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Brain insulin resistance: an early risk factor for Alzheimer's disease development in Down syndrome
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A Researcher’s guide to rodent models of Down syndrome: Recent insights and translational perspectives
Raza, M. A., Folz, A., Victorino, D. B., Xing, Z., Chen, X., Zuo, X., Borden, L. K., Potier, M., Mobley, W. C., Dierssen, M., et al. (2026) · STAR Protocols · doi:10.1016/j.xpro.2026.104717 · Cited by 5 · see citing works
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Authors: Tramutola, A., Lanzillotta, C., Di Domenico, F., Head, E., Butterfield, D. A., Perluigi, M., & Barone, E.
Affiliations: Sapienza University of Rome (IT)
University of California, Irvine (US)
University of Kentucky (US)
Corresponding author: Barone, Eugenio
ORCID: Tramutola, Antonella
Lanzillotta, Chiara
Head, Elizabeth
Butterfield, D. Allan
Perluigi, Marzia
Barone, Eugenio
Venue: Neurobiology of Disease
Publisher: Elsevier BV
Published: 2020-04
Volume: 137
Pages: 104772
ISSN: 0969-9961 (ISSN-L)
DOI: 10.1016/j.nbd.2020.104772
OpenAlex: W3002162723
Cited by: 73
References: 95
Citations by year: 2026: 4 · 2025: 11 · 2024: 11 · 2023: 13 · 2022: 9 · 2021: 12 · 2020: 13
FWCI: 8.81
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by-nc-nd)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD064993)
National Institute on Aging (AG055596, P50 AG16573)
Fondazione Umberto Veronesi
Sapienza Università di Roma (RM11715C77336E99, C26H15JT9X)
National Institutes of Health
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: brain insulin resistance, Down syndrome, early-onset Alzheimer's disease, insulin signaling pathway, insulin receptor, IRS-1, PTEN, GSK3β, protein kinase C, AS160, GLUT4, brain energy metabolism, hexokinase 2, mitochondrial protein complexes, syntaxin, APP cleavage, synaptic plasticity, neurodegeneration, cognitive impairment
MeSH terms: Adolescent, Adult, Aged, Alzheimer Disease, Brain, Child, Child, Preschool, Down Syndrome, Energy Metabolism, Female, Humans, Insulin Resistance, Male, Middle Aged, Receptor, Insulin, Signal Transduction, Young Adult

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Brain insulin resistance triggers early onset Alzheimer disease in Down syndrome

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