IGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome

Paula Araya; Kohl T Kinning; Christina Coughlan; Keith P Smith; Ross E Granrath; Belinda A Enriquez-Estrada; Kayleigh Worek; Kelly D Sullivan; Angela L Rachubinski; Kristine Wolter-Warmerdam; Francis Hickey; Matthew D Galbraith; Huntington Potter; Joaquin M Espinosa

doi:10.1016/j.celrep.2022.111883

IGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome

Cell Rep. 2022 Dec 27;41(13):111883. doi: 10.1016/j.celrep.2022.111883.

Authors

Affiliations

¹ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
² Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
³ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Alzheimer's and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁴ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Section of Developmental Biology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁵ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Section of Developmental Pediatrics, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁶ Sie Center for Down Syndrome, Department of Pediatrics, Children's Hospital Colorado, Aurora, CO 80045, USA.
⁷ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: joaquin.espinosa@cuanschutz.edu.

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.

Keywords: Alzheimer’s disease; CP: Developmental biology; CP: Neuroscience; autism; growth hormone; inflammation; insulin growth factor; mecasermin; neuroinflammation.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Biomarkers / metabolism
Down Syndrome* / genetics
Growth Disorders / genetics
Hearing Loss, Sensorineural
Humans
Insulin-Like Growth Factor I / deficiency
Insulin-Like Growth Factor I / genetics

IGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome

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