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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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Related in: MedlinePlus

Neuronal gene ontology groups distinguish the expression profiles of the aging human and mouse cortex.a. Neuronal gene ontology (GO) groups that are significantly enriched (p-value≤0.005; binomial approximated p-value for a hypergeometric distribution) for age-related expression changes (SAM comparison, FDR≤0.01) were identified. The X-axis represents the percentage of genes in a GO group with age-related up- or down-regulation. Multiple neuronal GO groups are enriched in the human aging profile; while only a few neuronal GO terms appear at less significant thresholds in the mouse aging profile. Age-upregulated and age-downregulated genes are shown separately. b. Number of genes in each GO group that are represented on the mouse and human microarray platforms.
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pone-0003329-g004: Neuronal gene ontology groups distinguish the expression profiles of the aging human and mouse cortex.a. Neuronal gene ontology (GO) groups that are significantly enriched (p-value≤0.005; binomial approximated p-value for a hypergeometric distribution) for age-related expression changes (SAM comparison, FDR≤0.01) were identified. The X-axis represents the percentage of genes in a GO group with age-related up- or down-regulation. Multiple neuronal GO groups are enriched in the human aging profile; while only a few neuronal GO terms appear at less significant thresholds in the mouse aging profile. Age-upregulated and age-downregulated genes are shown separately. b. Number of genes in each GO group that are represented on the mouse and human microarray platforms.

Mentions: As an independent line of evidence for age-related downregulation of neuronal genes, we identified Gene Ontology (GO) groups that were significantly enriched for age-related expression changes (Table S10). In total, 24 neuronal GO groups were significantly enriched for age-related expression changes in humans (hypergeometric p-value<0.005) (Fig. 4a). In contrast, only 5 of these 24 neuronal GO terms were slightly enriched for genes significantly associated with age in mice (hypergeometric p-value<0.05), despite similar or greater gene numbers for each GO term represented on mouse versus human microarrays (Fig. 4b). Further characterization of these GO terms revealed that the vast majority of genes in the human-enriched neuronal GO terms were downregulated with age. In contrast, the significant mouse neuronal GO terms were primarily enriched for age-upregulated genes (Fig. 4a). Thus, aging reduces the expression of genes with a variety of neuronal functions to a much greater extent in humans than mice.


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)

Neuronal gene ontology groups distinguish the expression profiles of the aging human and mouse cortex.a. Neuronal gene ontology (GO) groups that are significantly enriched (p-value≤0.005; binomial approximated p-value for a hypergeometric distribution) for age-related expression changes (SAM comparison, FDR≤0.01) were identified. The X-axis represents the percentage of genes in a GO group with age-related up- or down-regulation. Multiple neuronal GO groups are enriched in the human aging profile; while only a few neuronal GO terms appear at less significant thresholds in the mouse aging profile. Age-upregulated and age-downregulated genes are shown separately. b. Number of genes in each GO group that are represented on the mouse and human microarray platforms.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553198&req=5

pone-0003329-g004: Neuronal gene ontology groups distinguish the expression profiles of the aging human and mouse cortex.a. Neuronal gene ontology (GO) groups that are significantly enriched (p-value≤0.005; binomial approximated p-value for a hypergeometric distribution) for age-related expression changes (SAM comparison, FDR≤0.01) were identified. The X-axis represents the percentage of genes in a GO group with age-related up- or down-regulation. Multiple neuronal GO groups are enriched in the human aging profile; while only a few neuronal GO terms appear at less significant thresholds in the mouse aging profile. Age-upregulated and age-downregulated genes are shown separately. b. Number of genes in each GO group that are represented on the mouse and human microarray platforms.
Mentions: As an independent line of evidence for age-related downregulation of neuronal genes, we identified Gene Ontology (GO) groups that were significantly enriched for age-related expression changes (Table S10). In total, 24 neuronal GO groups were significantly enriched for age-related expression changes in humans (hypergeometric p-value<0.005) (Fig. 4a). In contrast, only 5 of these 24 neuronal GO terms were slightly enriched for genes significantly associated with age in mice (hypergeometric p-value<0.05), despite similar or greater gene numbers for each GO term represented on mouse versus human microarrays (Fig. 4b). Further characterization of these GO terms revealed that the vast majority of genes in the human-enriched neuronal GO terms were downregulated with age. In contrast, the significant mouse neuronal GO terms were primarily enriched for age-upregulated genes (Fig. 4a). Thus, aging reduces the expression of genes with a variety of neuronal functions to a much greater extent in humans than mice.

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