Abstract
BackgroundAge 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.HypothesisExpression levels of inflammatory, synaptic, and neurotrophic genes in the human brain are coordinated over the lifespan and underlie changes in phenotypic networks or cascades.MethodsWe 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.ResultsGene 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.ConclusionsCoordinated 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.
Highlights
The human brain changes structurally, functionally, and metabolically throughout the lifespan [1,2]
Expression of TRAF6 (TNF receptor associated factor 6), PLA2G4A, PTGS1, TLR4, APP, Microtubule-associated protein 2 (MAP2), and IL-1 receptor type 1 (IL1R1) increased while expression of MYD88, DBN1, RELA, PDGFA, and IFI16 decreased during Development but not Aging
Expression of glial fibrillary associated protein (GFAP), translator protein (TSPO), and IL-1 receptor antagonist (IL1RN) increased and of PTGS2, brain derived neurotropic factor protein (BDNF), IL1RAP, SYP, CX3CR1, and NOS2 decreased during Aging, without changing significantly with age during the Development interval
Summary
The human brain changes structurally, functionally, and metabolically throughout the lifespan [1,2]. Programmed dendritic growth followed by pruning, neuronal loss, shifts in energy metabolism from ketone body to glucose consumption, and rapid myelination occur during development [3,4,5,6]. Many of these changes are completed within the first two decades of life, myelination can continue into the fourth decade [5,7,8]. 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
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