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Evolution of the aging brain transcriptome and synaptic regulation.

Loerch PM, Lu T, Dakin KA, Vann JM, Isaacs A, Geula C, Wang J, Pan Y, Gabuzda DH, Li C, Prolla TA, Yankner BA - PLoS ONE (2008)

Bottom Line: Many of these age-regulated neuronal genes are associated with synaptic function.Gene downregulation was not associated with overall neuronal or synaptic loss.Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD) and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4). However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.

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Global repression of genes associated with GABA-mediated inhibitory neurotransmission.Shown are age-related changes in the expression of genes that mediate major neurotransmitter systems in the cortex of humans, rhesus monkeys, and mice. a. Genes involved in specific neurotransmitters were identified based on membership in the corresponding GO groups. Age-related fold changes in genes with orthologs in all three species and represented on all three microarray platforms are shown for humans, rhesus monkeys, and mice. Gene identities are provided in Table S11. *q-value≤0.01. b. Age-related fold changes for markers of inhibitory neuronal subpopulations. Statistical significance in a specific species (q-value≤0.01) is denoted with an asterisk.
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pone-0003329-g005: Global repression of genes associated with GABA-mediated inhibitory neurotransmission.Shown are age-related changes in the expression of genes that mediate major neurotransmitter systems in the cortex of humans, rhesus monkeys, and mice. a. Genes involved in specific neurotransmitters were identified based on membership in the corresponding GO groups. Age-related fold changes in genes with orthologs in all three species and represented on all three microarray platforms are shown for humans, rhesus monkeys, and mice. Gene identities are provided in Table S11. *q-value≤0.01. b. Age-related fold changes for markers of inhibitory neuronal subpopulations. Statistical significance in a specific species (q-value≤0.01) is denoted with an asterisk.

Mentions: Aging is associated with characteristic neurophysiologic and cognitive changes attributable to specific neurotransmitter systems. An important question, therefore, is whether age-related repression of neuronal genes selectively affects specific neurotransmitter systems. We noted that the only significantly enriched GO groups relating to a specific neurotransmitter were “GABA and GABA-A receptor activity” (Fig. 4). To explore this finding further, we examined the age-regulated expression of genes related to each of the major cortical neurotransmitters, including glutamate, gamma-aminobutyric acid (GABA), dopamine, glycine, serotonin, and acetylcholine (Fig. 5a). The most robustly age-regulated group corresponded to genes involved in GABA-mediated inhibitory neurotransmission (Fig. 5a and Table S11). Multiple genes in this category were age-downregulated with large fold changes in humans, including GABA A receptor subunits alpha 1 (GABRA1), alpha 5 (GABRA5), beta 3 (GABRB3) and gamma 2 (GABRG2), the GABA vesicular transporter (SLC32A1), and the GABA biosynthetic enzymes glutamate decarboxylase 1 and 2 (GAD1 and GAD2) (Table S11). Moreover, genes for the neuropeptides calbindin 1 (CALB1), somatostatin (SST), vasoactive intestinal peptide (VIP), cholecystokinin (CCK), tachykinin (TAC1), and nociceptin (PNOC), which are markers of inhibitory neuronal subpopulations in prefrontal cortex, were significantly age-downregulated (Fig. 5b). These genes were not significantly age-downregulated in mice, although some inhibitory markers, such as calbindin 1 and GABA A receptor subunit alpha 1, were significantly age-downregulated in rhesus macaques (Fig. 5). Downregulation of several glutamate-related genes, such as the glutamate receptor subunits AMPA 1 (GRIA1) and kainate 1 (GRIK1), was also observed, but the number and magnitude of these expression changes were less than that observed for GABA-related genes (Fig. 5a and Table S11). A subset of these age-related changes, notably calbindin 1, GABA A receptor subunit β3 and AMPA 1, have been confirmed by quantitative real time RT-PCR [6]. Thus, genes associated with inhibitory neurotransmission are repressed in the aging human cortex.


Evolution of the aging brain transcriptome and synaptic regulation.

Loerch PM, Lu T, Dakin KA, Vann JM, Isaacs A, Geula C, Wang J, Pan Y, Gabuzda DH, Li C, Prolla TA, Yankner BA - PLoS ONE (2008)

Global repression of genes associated with GABA-mediated inhibitory neurotransmission.Shown are age-related changes in the expression of genes that mediate major neurotransmitter systems in the cortex of humans, rhesus monkeys, and mice. a. Genes involved in specific neurotransmitters were identified based on membership in the corresponding GO groups. Age-related fold changes in genes with orthologs in all three species and represented on all three microarray platforms are shown for humans, rhesus monkeys, and mice. Gene identities are provided in Table S11. *q-value≤0.01. b. Age-related fold changes for markers of inhibitory neuronal subpopulations. Statistical significance in a specific species (q-value≤0.01) is denoted with an asterisk.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2553198&req=5

pone-0003329-g005: Global repression of genes associated with GABA-mediated inhibitory neurotransmission.Shown are age-related changes in the expression of genes that mediate major neurotransmitter systems in the cortex of humans, rhesus monkeys, and mice. a. Genes involved in specific neurotransmitters were identified based on membership in the corresponding GO groups. Age-related fold changes in genes with orthologs in all three species and represented on all three microarray platforms are shown for humans, rhesus monkeys, and mice. Gene identities are provided in Table S11. *q-value≤0.01. b. Age-related fold changes for markers of inhibitory neuronal subpopulations. Statistical significance in a specific species (q-value≤0.01) is denoted with an asterisk.
Mentions: Aging is associated with characteristic neurophysiologic and cognitive changes attributable to specific neurotransmitter systems. An important question, therefore, is whether age-related repression of neuronal genes selectively affects specific neurotransmitter systems. We noted that the only significantly enriched GO groups relating to a specific neurotransmitter were “GABA and GABA-A receptor activity” (Fig. 4). To explore this finding further, we examined the age-regulated expression of genes related to each of the major cortical neurotransmitters, including glutamate, gamma-aminobutyric acid (GABA), dopamine, glycine, serotonin, and acetylcholine (Fig. 5a). The most robustly age-regulated group corresponded to genes involved in GABA-mediated inhibitory neurotransmission (Fig. 5a and Table S11). Multiple genes in this category were age-downregulated with large fold changes in humans, including GABA A receptor subunits alpha 1 (GABRA1), alpha 5 (GABRA5), beta 3 (GABRB3) and gamma 2 (GABRG2), the GABA vesicular transporter (SLC32A1), and the GABA biosynthetic enzymes glutamate decarboxylase 1 and 2 (GAD1 and GAD2) (Table S11). Moreover, genes for the neuropeptides calbindin 1 (CALB1), somatostatin (SST), vasoactive intestinal peptide (VIP), cholecystokinin (CCK), tachykinin (TAC1), and nociceptin (PNOC), which are markers of inhibitory neuronal subpopulations in prefrontal cortex, were significantly age-downregulated (Fig. 5b). These genes were not significantly age-downregulated in mice, although some inhibitory markers, such as calbindin 1 and GABA A receptor subunit alpha 1, were significantly age-downregulated in rhesus macaques (Fig. 5). Downregulation of several glutamate-related genes, such as the glutamate receptor subunits AMPA 1 (GRIA1) and kainate 1 (GRIK1), was also observed, but the number and magnitude of these expression changes were less than that observed for GABA-related genes (Fig. 5a and Table S11). A subset of these age-related changes, notably calbindin 1, GABA A receptor subunit β3 and AMPA 1, have been confirmed by quantitative real time RT-PCR [6]. Thus, genes associated with inhibitory neurotransmission are repressed in the aging human cortex.

Bottom Line: Many of these age-regulated neuronal genes are associated with synaptic function.Gene downregulation was not associated with overall neuronal or synaptic loss.Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD) and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4). However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.

Show MeSH
Related in: MedlinePlus