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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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Age-regulated genes common to humans, rhesus macaques, and mice.The transcriptional profiles of genes that are age-regulated in all three species were analyzed by hierarchical clustering. Reduced expressed with aging is indicated by a transition from red in the young to blue in the aged, and vice versa. Genes separate into three groups based on whether the direction of age-related changes (i.e., age-upregulated or age-downregulated) is conserved in all three species (category I), changes between mice and rhesus macaques (category II), or changes between rhesus macaques and humans (category III). Also indicated is the evolutionary time of divergence in years for each pair of species based on analysis of protein sequence alignments [37].
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pone-0003329-g002: Age-regulated genes common to humans, rhesus macaques, and mice.The transcriptional profiles of genes that are age-regulated in all three species were analyzed by hierarchical clustering. Reduced expressed with aging is indicated by a transition from red in the young to blue in the aged, and vice versa. Genes separate into three groups based on whether the direction of age-related changes (i.e., age-upregulated or age-downregulated) is conserved in all three species (category I), changes between mice and rhesus macaques (category II), or changes between rhesus macaques and humans (category III). Also indicated is the evolutionary time of divergence in years for each pair of species based on analysis of protein sequence alignments [37].

Mentions: Hierarchical clustering of the common age-regulated genes demonstrated that they fall into three distinct groups: I. Age-regulated genes that are conserved among all three species. II. Genes that change with age in all 3 species but differ in directionality between mouse and rhesus (e.g., from age-downregulated to age-upregulated); and III. Age-regulated genes that change directionality between rhesus and human (Fig. 2 and Table 1). Among the category I genes conserved in all 3 species, the most robustly age-upregulated gene was the anti-oxidant lipid binding protein apolipoprotein D. The most robustly age-downregulated genes in the conserved category were CAMK4, a component of synaptic cAMP-mediated signaling, and ARPP-21, a phosphoprotein also implicated in neuronal cAMP signaling [14] (Table 1). The genes in category II were composed almost entirely of genes that are age-upregulated in mice and downregulated in both rhesus monkeys and humans, defining a set of age-related gene expression changes common to rhesus monkeys and humans. The most robustly downregulated of these primate aging genes was calbindin 1 (CALB1), a marker of cortical inhibitory interneurons (Table 1).


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)

Age-regulated genes common to humans, rhesus macaques, and mice.The transcriptional profiles of genes that are age-regulated in all three species were analyzed by hierarchical clustering. Reduced expressed with aging is indicated by a transition from red in the young to blue in the aged, and vice versa. Genes separate into three groups based on whether the direction of age-related changes (i.e., age-upregulated or age-downregulated) is conserved in all three species (category I), changes between mice and rhesus macaques (category II), or changes between rhesus macaques and humans (category III). Also indicated is the evolutionary time of divergence in years for each pair of species based on analysis of protein sequence alignments [37].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003329-g002: Age-regulated genes common to humans, rhesus macaques, and mice.The transcriptional profiles of genes that are age-regulated in all three species were analyzed by hierarchical clustering. Reduced expressed with aging is indicated by a transition from red in the young to blue in the aged, and vice versa. Genes separate into three groups based on whether the direction of age-related changes (i.e., age-upregulated or age-downregulated) is conserved in all three species (category I), changes between mice and rhesus macaques (category II), or changes between rhesus macaques and humans (category III). Also indicated is the evolutionary time of divergence in years for each pair of species based on analysis of protein sequence alignments [37].
Mentions: Hierarchical clustering of the common age-regulated genes demonstrated that they fall into three distinct groups: I. Age-regulated genes that are conserved among all three species. II. Genes that change with age in all 3 species but differ in directionality between mouse and rhesus (e.g., from age-downregulated to age-upregulated); and III. Age-regulated genes that change directionality between rhesus and human (Fig. 2 and Table 1). Among the category I genes conserved in all 3 species, the most robustly age-upregulated gene was the anti-oxidant lipid binding protein apolipoprotein D. The most robustly age-downregulated genes in the conserved category were CAMK4, a component of synaptic cAMP-mediated signaling, and ARPP-21, a phosphoprotein also implicated in neuronal cAMP signaling [14] (Table 1). The genes in category II were composed almost entirely of genes that are age-upregulated in mice and downregulated in both rhesus monkeys and humans, defining a set of age-related gene expression changes common to rhesus monkeys and humans. The most robustly downregulated of these primate aging genes was calbindin 1 (CALB1), a marker of cortical inhibitory interneurons (Table 1).

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