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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

Cell type localization of gene expression in the aging cortex.Genes enriched in specific cortical cell types, based on the Allen Brain Atlas, were analyzed in the aging mouse and human gene expression profiles. The percentage of age-regulated genes enriched in each cell type is represented by the Y-axis was determined as described in Methods. The expected percentages are indicated by the dashed line. Statistically significant cell type enrichment was determined using a Chi-square test with a permutation-based p-value (1,000 replicates). Specific cell types that exhibit a statistically significant change in age-regulated genes are indicated by an asterisk.
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pone-0003329-g003: Cell type localization of gene expression in the aging cortex.Genes enriched in specific cortical cell types, based on the Allen Brain Atlas, were analyzed in the aging mouse and human gene expression profiles. The percentage of age-regulated genes enriched in each cell type is represented by the Y-axis was determined as described in Methods. The expected percentages are indicated by the dashed line. Statistically significant cell type enrichment was determined using a Chi-square test with a permutation-based p-value (1,000 replicates). Specific cell types that exhibit a statistically significant change in age-regulated genes are indicated by an asterisk.

Mentions: The agreement between the human and mouse cell-type enrichment datasets enabled us to use the Allen Brain Atlas to localize age-related gene expression changes in both species. The limited number of age-related changes in the rhesus dataset prevented us from conducting a comprehensive cell type analysis in rhesus macaques. To determine whether there is a relationship between age-related expression changes and cell type localization, we determined the number of age-related gene expression changes that could be localized to each cell type using the Allen Brain Atlas. A relationship between age-related expression changes and cell type localization was analyzed statistically by determining if the number of age-regulated genes enriched in specific cell types deviated significantly from the number expected if these changes were independent of cell type localization. Both the human and mouse localization analysis showed significant deviation from values expected under the independence assumption (p-value<0.05). Statistical significance was assessed using a Chi-squared test in which the distribution was estimated based on 1,000 replications (see Methods). The primary data and hypergeometric-based estimates are provided in Tables S8 and S9, respectively. Both humans and mice exhibit a larger fraction of age-upregulated astrocyte- and oligodendrocyte-enriched genes, and age-downregulated neuron-enriched genes, than would be expected by chance alone (Fig. 3). However, relative to mice, human aging is distinguished by a dramatic increase in the proportion of neuron-enriched downregulated genes (Fig. 3). This was also observed when the data was stratified by gender (Text S2). Analysis of our data using a different cell type transcriptome database, derived by isolation of astrocytes, neurons and oligodendrocytes from transgenic mouse cortex [17], confirmed that downregulation of neuronal genes distinguishes aging humans from aging mice (data not shown).


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)

Cell type localization of gene expression in the aging cortex.Genes enriched in specific cortical cell types, based on the Allen Brain Atlas, were analyzed in the aging mouse and human gene expression profiles. The percentage of age-regulated genes enriched in each cell type is represented by the Y-axis was determined as described in Methods. The expected percentages are indicated by the dashed line. Statistically significant cell type enrichment was determined using a Chi-square test with a permutation-based p-value (1,000 replicates). Specific cell types that exhibit a statistically significant change in age-regulated genes are indicated by an asterisk.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003329-g003: Cell type localization of gene expression in the aging cortex.Genes enriched in specific cortical cell types, based on the Allen Brain Atlas, were analyzed in the aging mouse and human gene expression profiles. The percentage of age-regulated genes enriched in each cell type is represented by the Y-axis was determined as described in Methods. The expected percentages are indicated by the dashed line. Statistically significant cell type enrichment was determined using a Chi-square test with a permutation-based p-value (1,000 replicates). Specific cell types that exhibit a statistically significant change in age-regulated genes are indicated by an asterisk.
Mentions: The agreement between the human and mouse cell-type enrichment datasets enabled us to use the Allen Brain Atlas to localize age-related gene expression changes in both species. The limited number of age-related changes in the rhesus dataset prevented us from conducting a comprehensive cell type analysis in rhesus macaques. To determine whether there is a relationship between age-related expression changes and cell type localization, we determined the number of age-related gene expression changes that could be localized to each cell type using the Allen Brain Atlas. A relationship between age-related expression changes and cell type localization was analyzed statistically by determining if the number of age-regulated genes enriched in specific cell types deviated significantly from the number expected if these changes were independent of cell type localization. Both the human and mouse localization analysis showed significant deviation from values expected under the independence assumption (p-value<0.05). Statistical significance was assessed using a Chi-squared test in which the distribution was estimated based on 1,000 replications (see Methods). The primary data and hypergeometric-based estimates are provided in Tables S8 and S9, respectively. Both humans and mice exhibit a larger fraction of age-upregulated astrocyte- and oligodendrocyte-enriched genes, and age-downregulated neuron-enriched genes, than would be expected by chance alone (Fig. 3). However, relative to mice, human aging is distinguished by a dramatic increase in the proportion of neuron-enriched downregulated genes (Fig. 3). This was also observed when the data was stratified by gender (Text S2). Analysis of our data using a different cell type transcriptome database, derived by isolation of astrocytes, neurons and oligodendrocytes from transgenic mouse cortex [17], confirmed that downregulation of neuronal genes distinguishes aging humans from aging mice (data not shown).

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