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Cited by 230Alzheimer's disease research and treatmentsDown syndrome and intellectual disability researchNeuroinflammation and Neurodegeneration Mechanisms

Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis

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Wilcock, Donna M, Griffin, W Sue T·2013·Journal of Neuroinflammation
DOI 10.1186/1742-2094-10-84PMC PMC3750399
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Abstract

Down syndrome (DS) is the result of triplication of chromosome 21 (trisomy 21) and is the prevailing cause of mental retardation. In addition to the mental deficiencies and physical anomalies noted at birth, triplication of chromosome 21 gene products results in the neuropathological and cognitive changes of Alzheimer's disease (AD). Mapping of the gene that encodes the precursor protein (APP) of the β-amyloid (Aβ) present in the Aβ plaques in both AD and DS to chromosome 21 was strong evidence that this chromosome 21 gene product was a principal neuropathogenic culprit in AD as well as DS. The discovery of neuroinflammatory changes, including dramatic proliferation of activated glia overexpressing a chromosome 2 gene product--the pluripotent immune cytokine interleukin-1 (IL-1)--and a chromosome 21 gene product--S100B--in the brains of fetuses, neonates, and children with DS opened the possibility that early events in Alzheimer pathogenesis were driven by cytokines. The specific chromosome 21 gene products and the complexity of the mechanisms they engender that give rise to the neuroinflammatory responses noted in fetal development of the DS brain and their potential as accelerators of Alzheimer neuropathogenesis in DS are topics of this review, particularly as they relate to development and propagation of neuroinflammation, the consequences of which are recognized clinically and neuropathologically as Alzheimer's disease.

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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 [10]

    The Introduction reports glial activation and excessive inflammatory cytokine expression in DS fetuses, infants, and children; its Summary specifies activated microglia and astrocytes. Our copy does not establish the claimed defects in neuronal development, increased inhibitory-to-excitatory neuron ratio, or altered dendritic spine dynamics. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Individuals with Down syndrome (T21) are strongly predisposed to Alzheimer's disease, with nearly all exhibiting AD-related neuropathological features by age ∼40 and highly variable onset of dementia thereafter.

    “Individuals with Down syndrome (DS), caused by trisomy of chromosome 21 (chr21, T21), are strongly predisposed to Alzheimer’s disease (AD), due to triplication of the APP gene, with ∼100% penetrance of AD brain pathology by age 40 and variable onset of dementia thereafter.”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [10]

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Authors
Wilcock, D. M., & Griffin, W. S. T.
Affiliations
  • University of Kentucky (US)
  • University of Arkansas for Medical Sciences (US)
Corresponding author
Griffin, W Sue T
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2013-07-16
Volume
10
Issue
1
Pages
84-84
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/1742-2094-10-84
PMC
PMC3750399
OpenAlex
W2110608677
Cited by
230
References
143
Citations by year
2026: 4 · 2025: 18 · 2024: 21 · 2023: 12 · 2022: 15 · 2021: 26 · 2020: 22 · 2019: 11 · 2018: 24 · 2017: 14 · 2016: 17 · 2015: 18 · 2014: 25 · 2013: 3
FWCI
2.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
Funders
  • Windgate Foundation
  • National Institutes of Health (AG12411)
  • National Institute on Aging (NIH/NIA AG12411, AG 12411, NIA AG12411)
  • National Institute of General Medical Sciences (P20GM103486)
  • National Institute of Neurological Disorders and Stroke (NS079637, R01NS079637)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Down syndrome, neuroinflammation, Alzheimer's disease, amyloid precursor protein, amyloid plaques, interleukin-1, S100B, glial activation, cytokines, fetal brain development
MeSH terms
Alzheimer Disease, Chromosomes, Human, Pair 21, Down Syndrome, Humans, Inflammation

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