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Anticipated brain molecular aging in major depression.

ABSTRACT: OBJECTIVES:Brain molecular aging, the pervasive and consistent transcriptome changes associated with normal brain aging, appears to overlap with disease pathways and may be anticipated in neurodegenerative and neuropsychiatric diseases, including major depressive disorder (MDD). Here, we characterize the global interaction of MDD-related gene changes with age, starting from our previous report of downregulated brain-derived neurotrophic factor (BDNF) and BDNF-dependent genes in the amygdala of women with MDD. METHODS:A large-scale gene expression data set in the amygdala from a postmortem cohort of 21 women with MDD and 21 age-matched controls (age range: 16-74 years) was analyzed for correlations of gene transcript changes with age, in the presence or absence of a diagnosis of MDD. RESULTS:1) The age-related decrease in BDNF transcripts observed in control subjects corresponds with further age-related decreases in BDNF and BDNF-dependent gene expression in MDD subjects; 2) most MDD-related genes are frequently age-regulated in both MDD and control subjects; 3) the effects of MDD and age are positively correlated; 4) most genes that are age-dependent in control subjects display greater age effects in MDD subjects; and 5) the increased prevalence of age effects in MDD corresponds to similar trends in controls, rather than representing de novo age effects. CONCLUSIONS:MDD strongly associates with robust and anticipated gene expression changes that occur during normal aging of the brain, suggesting that an older molecular age of the brain represents an early biological event and/or a marker of risk for subsequent onset of MDD symptoms.

SUBMITTER: Douillard-Guilloux G

PROVIDER: S-EPMC3615087 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Anticipated brain molecular aging in major depression.

Douillard-Guilloux Gaëlle G Guilloux Jean-Philippe JP Lewis David A DA Sibille Etienne E

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 20130206 5

<h4>Objectives</h4>Brain molecular aging, the pervasive and consistent transcriptome changes associated with normal brain aging, appears to overlap with disease pathways and may be anticipated in neurodegenerative and neuropsychiatric diseases, including major depressive disorder (MDD). Here, we characterize the global interaction of MDD-related gene changes with age, starting from our previous report of downregulated brain-derived neurotrophic factor (BDNF) and BDNF-dependent genes in the amygd ...[more]

PMID: 23570888

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Project description:Brain gene expression profiling studies of suicide and depression using oligonucleotide microarrays have often failed to distinguish these two phenotypes. Moreover, next generation sequencing approaches are more accurate in quantifying gene expression and can detect alternative splicing. Using RNA-seq, we examined whole-exome gene and exon expression in non-psychiatric controls (CON, N=29), DSM-IV major depressive disorder suicides (MDD-S, N=21) and MDD non-suicides (MDD, N=9) in the dorsal lateral prefrontal cortex (Brodmann Area 9) of sudden death medication-free individuals post mortem. Using small RNA-seq, we also examined miRNA expression (nine samples per group). DeSeq2 identified 35 genes differentially expressed between groups and surviving adjustment for false discovery rate (adjusted P<0.1). In depression, altered genes include humanin-like-8 (MTRNRL8), interleukin-8 (IL8), and serpin peptidase inhibitor, clade H (SERPINH1) and chemokine ligand 4 (CCL4), while exploratory gene ontology (GO) analyses revealed lower expression of immune-related pathways such as chemokine receptor activity, chemotaxis and cytokine biosynthesis, and angiogenesis and vascular development in (adjusted P<0.1). Hypothesis-driven GO analysis suggests lower expression of genes involved in oligodendrocyte differentiation, regulation of glutamatergic neurotransmission, and oxytocin receptor expression in both suicide and depression, and provisional evidence for altered DNA-dependent ATPase expression in suicide only. DEXSEq analysis identified differential exon usage in ATPase, class II, type 9B (adjusted P<0.1) in depression. Differences in miRNA expression or structural gene variants were not detected. Results lend further support for models in which deficits in microglial, endothelial (blood-brain barrier), ATPase activity and astrocytic cell functions contribute to MDD and suicide, and identify putative pathways and mechanisms for further study in these disorder

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Anticipated brain molecular aging in major depression.

Publications

Anticipated brain molecular aging in major depression.

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