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Cited by 138Neuroinflammation and Neurodegeneration MechanismsDown syndrome and intellectual disability researchAlzheimer's disease research and treatments

Evolution of neuroinflammation across the lifespan of individuals with Down syndrome

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Flores-Aguilar, Lisi, Iulita, M Florencia, Kovecses, Olivia, Torres, Maria D, Levi, Sarah M, Zhang, Yian, Askenazi, Manor, Wisniewski, Thomas +2 more·2020·Brain
DOI 10.1093/brain/awaa326PMC PMC7805813
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Abstract

Epidemiological and experimental studies suggest that a disease-aggravating neuroinflammatory process is present at preclinical stages of Alzheimer’s disease. Given that individuals with Down syndrome are at increased genetic risk of Alzheimer’s disease and therefore develop the spectrum of Alzheimer’s neuropathology in a uniform manner, they constitute an important population to study the evolution of neuroinflammation across the Alzheimer’s continuum. Therefore, in this cross-sectional study, we characterized the brain inflammatory profile across the lifespan of individuals with Down syndrome. Microglial morphology and inflammatory cytokine expression were analysed by immunohistochemistry and electrochemiluminescent-based immunoassays in the frontal cortex from foetuses to adults with Down syndrome and control subjects (16 gestational weeks to 64 years), totalling 127 cases. Cytokine expression in mixed foetal primary cultures and hippocampus of adults with Down syndrome, as well as the effects of sex on cytokine expression were also analysed. A higher microglial soma size-to-process length ratio was observed in the frontal cortex of children and young adults with Down syndrome before the development of full-blown Alzheimer’s pathology. Moreover, young adults with Down syndrome also displayed increased numbers of rod-like microglia. Increased levels of interleukin-8 and interleukin-10 were observed in children with Down syndrome (1–10 years; Down syndrome n = 5, controls n = 10) and higher levels of interleukin-1β, interleukin-1α, interleukin-6, interleukin-8, interleukin-10, interleukin-15, eotaxin-3, interferon gamma-induced protein 10, macrophage-derived chemokine, and macrophage inflammatory protein-beta, were found in young adults with Down syndrome compared to euploid cases (13–25 years, Down syndrome n = 6, controls n = 24). Increased cytokine expression was also found in the conditioned media of mixed cortical primary cultures from second trimester foetuses with Down syndrome (Down syndrome n = 7, controls n = 7). Older adults with Down syndrome (39–68 years, Down syndrome n = 22, controls n = 16) displayed reduced levels of interleukin-10, interleukin-12p40, interferon-gamma and tumour necrosis factor-alpha. Microglia displayed larger somas and shorter processes. Moreover, an increase in dystrophic microglia and rod-like microglia aligning to neurons harbouring tau pathology were also observed. Sex stratification analyses revealed that females with Down syndrome had increased interleukin-6 and interleukin-8 levels compared to males with Down syndrome. Finally, multivariate projection methods identified specific cytokine patterns among individuals with Down syndrome. Our findings indicate the presence of an early and evolving neuroinflammatory phenotype across the lifespan in Down syndrome, a knowledge that is relevant for the discovery of stage-specific targets and for the design of possible anti-inflammatory trials against Alzheimer’s disease in this population.

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  • Inflammatory cytokine levels in post-mortem tissue from fetuses and children with DS are increased relative to age-matched controls.

    “It has been shown that the levels of inflammatory cytokines in post-mortem tissue from fetuses and children with DS are increased relative to age-matched controls, suggesting that microglia may become hyperactivated in the developing DS brain147 (see also Box 4).”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [147]

    In “Altered microglial phenotype and increased brain cytokine expression in children with Down syndrome” (page not provided), the paper reports significantly higher IL-8 and IL-10 in post-mortem frontal cortex from children with Down syndrome. The same section reports no significant difference in inflammatory markers in foetal brain homogenates versus controls. Increased cytokines in foetal cortical cell-culture media do not establish the claimed increase in post-mortem foetal tissue. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • 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 [22]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Microglia in the frontal cortex of children with DS have increased soma size relative to controls.

    “Furthermore, microglia in the frontal cortex of children with DS have increased soma size relative to controls, indicative of a distinct morphology and potential overactivation147.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [147]

  • The raised levels of APOE are consistent with a growing body of data indicating that the neuroimmune system differs in people with DS.

    “The raised levels of APOE are consistent with a growing body of data indicating that the neuroimmune system differs in people with DS [15, 34, 46, 51, 53, 66, 67].”

    From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [15]

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Authors
Flores-Aguilar, L., Iulita, M. F., Kovecses, O., Torres, M. D., Levi, S. M., Zhang, Y., Askenazi, M., Wisniewski, T., Busciglio, J., & Cuello, A. C.
Affiliations
  • Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
  • Universitat Autònoma de Barcelona (ES)
  • McGill University (CA)
  • University of California, Irvine (US)
  • New York University (US)
  • Biomedical Hosting LLC, Arlington, USA
  • Departments of Neurology, Pathology, and Psychiatry, Center for Cognitive Neurology, New York University, Grossman School of Medicine, New York, USA
  • University of Oxford (GB)
Corresponding author
Cuello, A Claudio
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2020-11-18
Volume
143
Issue
12
Pages
3653-3671
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awaa326
PMC
PMC7805813
OpenAlex
W3101792118
Cited by
138
References
115
Citations by year
2026: 19 · 2025: 30 · 2024: 29 · 2023: 17 · 2022: 21 · 2021: 21 · 2020: 1
FWCI
6.00
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Brain (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Doctoral Merit Scholarship Program for Foreign Students
  • Fonds de Recherche du Quebec–Nature et technologies
  • National Council of Science and Technology
  • Jérôme Léjeune Foundation
  • Fonds de Recherche du Quebec-Santé
  • T-32 ‘Training in the Neurobiology of Aging’ (AG000096)
  • McGill University
  • National Institute on Aging – National Institutes of Health (1R01AG056850-01A1)
  • Alzheimer's Disease Research Center (AG16573 and AG08051)
  • Canadian Institutes of Health Research (MOP-97776)
  • Alzheimer Society of Canada (241755)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • 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
Keywords
Down syndrome, neuroinflammation, Alzheimer's disease, microglial morphology, inflammatory cytokines, interleukin-8, IL-10, IL-1β, sex differences, lifespan, frontal cortex, hippocampus
MeSH terms
Adolescent, Aged, Aging, Alzheimer Disease, Cells, Cultured, Child, Child, Preschool, Cross-Sectional Studies, Down Syndrome, Encephalitis, Female, Hippocampus, Humans, Infant, Infant, Newborn, Longevity, Male, Middle Aged, Pregnancy, Cytokines, Microglia, Disease Progression, Tauopathies, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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