Gene expression profiling in the adult Down syndrome brain

Abstract

The mechanisms by which trisomy 21 leads to the characteristic Down syndrome (DS) phenotype are unclear. We used whole genome microarrays to characterize for the first time the transcriptome of human adult brain tissue (dorsolateral prefrontal cortex) from seven DS subjects and eight controls. These data were coanalyzed with a publicly available dataset from fetal DS tissue and functional profiling was performed to identify the biological processes central to DS and those that may be related to late onset pathologies, particularly Alzheimer disease neuropathology. A total of 685 probe sets were differentially expressed between adult DS and control brains at a stringent significance threshold (adjusted p value (q) < 0.005), 70% of these being up-regulated in DS. Over 25% of genes on chromosome 21 were differentially expressed in comparison to a median of 4.4% for all chromosomes. The unique profile of up-regulation on chromosome 21, consistent with primary dosage effects, was accompanied by widespread transcriptional disruption. The critical Alzheimer disease gene, APP, located on chromosome 21, was not found to be up-regulated in adult brain by microarray or QPCR analysis. However, numerous other genes functionally linked to APP processing were dysregulated. Functional profiling of genes dysregulated in both fetal and adult datasets identified categories including development (notably Notch signaling and Dlx family genes), lipid transport, and cellular proliferation. In the adult brain these processes were concomitant with cytoskeletal regulation and vesicle trafficking categories, and increased immune response and oxidative stress response, which are likely linked to the development of Alzheimer pathology in individuals with DS.

Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses

“…We see widespread differential expression of genes from the other diploid chromosomes (Fig. 2B), consistent with the results of Gardiner (37) and Lockstone et al (29). Hierarchical clustering of our samples based on expression levels of the 409 Individual genes not located on chromosome 21 completely separates the DS samples from the controls (as seen in Fig.…”

“…Because individuals with DS demonstrate pathology consistent with Alzheimer disease at an early age (28), links to the role of oxidative stress in Alzheimer's have been explored (27). Lockstone et al (29) found that oxidative stress response genes were over-represented in adult but not fetal DS tissue, and suggested that this response might reflect adult-onset DS pathologies such as Alzheimer disease. More recently, a few groups (16,30) have found oxidative stress response markers in fetal DS tissues, although neither study emphasized this particular result or considered the potential relationship between oxidative stress and other functional pathways.…”

Attenuation of Notch signalling by the Down-syndrome-associated kinase DYRK1A

“…Interestingly, our data may be also relevant for studies of Down syndrome (DS). Indeed, DYRK1A is one of the genes located in the Down syndrome critical region (Delabar et al, 1993) and its expression is upregulated in DS individuals (Dowjat et al, 2007;Lockstone et al, 2007). Notch signalling is also altered in the DS condition, although contrasting data have been obtained in studies in humans and mouse models.…”

Genome Profiling and Potential Biomarkers in Neurodegenerative Disorders

“…Additionally, it is important that in most instances, a complete triplication of genes located on chromosome 21 may dominate genes commonly dysregulated in DS and AD [29]. Also, the number of brain tissue samples samples profiled in microarray experiments was by far the lowest among other types of NDG diseases investigated in our survey.…”