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Cited by 50Down syndrome and intellectual disability researchGrowth Hormone and Insulin-like Growth FactorsAlzheimer's disease research and treatments

IGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome

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Araya, Paula, Kinning, Kohl T., Coughlan, Christina, Smith, Keith P., Granrath, Ross E., Enriquez-Estrada, Belinda A., Worek, Kayleigh, Sullivan, Kelly D. +6 more·2022·Cell Reports
DOI 10.1016/j.celrep.2022.111883PMC PMC9876612
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Abstract

Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by stunted growth, cognitive impairment, and increased risk of diverse neurological conditions. Although signs of lifelong neurodegeneration are well documented in DS, the mechanisms underlying this phenotype await elucidation. Here we report a multi-omics analysis of neurodegeneration and neuroinflammation biomarkers, plasma proteomics, and immune profiling in a diverse cohort of more than 400 research participants. We identified depletion of insulin growth factor 1 (IGF1), a master regulator of growth and brain development, as the top biosignature associated with neurodegeneration in DS. Individuals with T21 display chronic IGF1 deficiency downstream of growth hormone production, associated with a specific inflammatory profile involving elevated tumor necrosis factor alpha (TNF-α). Shorter children with DS show stronger IGF1 deficiency, elevated biomarkers of neurodegeneration, and increased prevalence of autism and other conditions. These results point to disruption of IGF1 signaling as a potential contributor to stunted growth and neurodegeneration in DS.

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  • There is substantial evidence of neuropathology from early in life in DS, including defects in neuronal development, increased ratio of inhibitory to excitatory neurons, alterations in neuronal dendritic spine dynamics, activation of microglia, astrocyte reactivity, and elevated production of inflammatory cytokines in the brain.

    “There is substantial evidence of neuropathology from early in life in DS,6,9,10,21 including defects in neuronal development, an increased ratio of inhibitory to excitatory neurons, alterations in neuronal dendritic spines dynamics, activation of microglia, astrocyte reactivity, and elevated production of inflammatory cytokines in the brain.22,23,24,25”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [21]

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Cited by

Sorted by citations

Authors
Araya, P., Kinning, K. T., Coughlan, C., Smith, K. P., Granrath, R. E., Enriquez-Estrada, B. A., Worek, K., Sullivan, K. D., Rachubinski, A. L., Wolter-Warmerdam, K., Hickey, F., Galbraith, M. D., Potter, H., & Espinosa, J. M.
Affiliations
  • University of Colorado Anschutz (US)
  • Children's Hospital Colorado (US)
Corresponding author
Espinosa, Joaquin M.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2022-12
Volume
41
Issue
13
Pages
111883
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2022.111883
PMC
PMC9876612
OpenAlex
W4313255504
Cited by
50
References
8
Citations by year
2026: 11 · 2025: 14 · 2024: 13 · 2023: 8 · 2022: 4
FWCI
9.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (UL1TR002535)
  • National Cancer Institute (P30CA046934)
  • National Institute of Allergy and Infectious Diseases (R01AI145988, R01AI150305)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Down syndrome, insulin-like growth factor I, neurodegeneration, growth arrest, neuroinflammation, plasma proteomics, immune profiling, TNF-α, growth hormone, autism spectrum disorder, biomarkers
MeSH terms
Down Syndrome, Growth Disorders, Hearing Loss, Sensorineural, Humans, Insulin-Like Growth Factor I, Biomarkers

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