Coordinated Gene Expression of Neuroinflammatory and Cell Signaling Markers in Dorsolateral Prefrontal Cortex during Human Brain Development and Aging
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BACKGROUND: Age changes in expression of inflammatory, synaptic, and neurotrophic genes are not well characterized during human brain development and senescence. Knowing these changes may elucidate structural, metabolic, and functional brain processes over the lifespan, as well vulnerability to neurodevelopmental or neurodegenerative diseases. HYPOTHESIS: Expression levels of inflammatory, synaptic, and neurotrophic genes in the human brain are coordinated over the lifespan and underlie changes in phenotypic networks or cascades. METHODS: We used a large-scale microarray dataset from human prefrontal cortex, BrainCloud, to quantify age changes over the lifespan, divided into Development (0 to 21 years, 87 brains) and Aging (22 to 78 years, 144 brains) intervals, in transcription levels of 39 genes. RESULTS: Gene expression levels followed different trajectories over the lifespan. Many changes were intercorrelated within three similar groups or clusters of genes during both Development and Aging, despite different roles of the gene products in the two intervals. During Development, changes were related to reported neuronal loss, dendritic growth and pruning, and microglial events; TLR4, IL1R1, NFKB1, MOBP, PLA2G4A, and PTGS2 expression increased in the first years of life, while expression of synaptic genes GAP43 and DBN1 decreased, before reaching plateaus. During Aging, expression was upregulated for potentially pro-inflammatory genes such as NFKB1, TRAF6, TLR4, IL1R1, TSPO, and GFAP, but downregulated for neurotrophic and synaptic integrity genes such as BDNF, NGF, PDGFA, SYN, and DBN1. CONCLUSIONS: Coordinated changes in gene transcription cascades underlie changes in synaptic, neurotrophic, and inflammatory phenotypic networks during brain Development and Aging. Early postnatal expression changes relate to neuronal, glial, and myelin growth and synaptic pruning events, while late Aging is associated with pro-inflammatory and synaptic loss changes. Thus, comparable transcriptional regulatory networks that operate throughout the lifespan underlie different phenotypic processes during Aging compared to Development.
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Aged microglia in humans and mice adopt a pro-inflammatory profile including higher expression of TNFα, IL-6, IL-1β, and markers of priming such as CD11b and MHC-II.
“In both humans [62] and mice [52,63,64], aged microglia adopt a pro-inflammatory profile including higher expression of genes including TNFα, IL-6, and IL-1β, as well as markers of ‘priming’ such as CD11b and MHC-II (Figure 1).”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [62]
Microarray studies of the adult and aged human prefrontal cortex reported age-dependent increased expression of inflammation-associated genes, such as NFKB, Toll-like-receptor (TLR)-4, IL-1R, and GFAP.
“For instance, microarray studies of the adult and aged human prefrontal cortex reported age-dependent increased expression of inflammation-associated genes, such as, NFKB, Toll-like-receptor (TLR)-4, IL-1R, and GFAP (Primiani et al, 2014).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Primiani et al, 2014
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- [105]Rao JS, Harry GJ, Rapoport SI, Kim H-W (2009) Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Molecular psychiatry PMC2844920 19488045
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Untangling senescent and damage‐associated microglia in the aging and diseased brain
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- Authors
- Primiani, C. T., Ryan, V. H., Rao, J. S., Cam, M. C., Ahn, K., Modi, H. R., & Rapoport, S. I.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Primiani, Christopher T.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-10-20
- Volume
- 9
- Issue
- 10
- Pages
- e110972
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4203852
- OpenAlex
- W2053005781
- Cited by
- 56
- References
- 114
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 6 · 2018: 1 · 2017: 6 · 2016: 8 · 2015: 3
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute on Aging
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- human brain development, brain aging, dorsolateral prefrontal cortex, gene expression, neuroinflammation, synaptic genes, transcriptional regulatory networks, TLR4, IL1R1, NFKB1, brain-derived neurotrophic factor, synaptic pruning, microglia, neurodegeneration, neurodevelopmental disorders
- MeSH terms
- Adolescent, Adult, Aged, Aging, Child, Child, Preschool, Female, Gene Expression Regulation, Humans, Infant, Infant, Newborn, Inflammation, Male, Middle Aged, Nerve Tissue Proteins, Signal Transduction, Prefrontal Cortex
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.
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