Abstract
Various coding genes representing multiple functional categories are downregulated in blood mononuclear cells (BMC) of patients with sporadic Alzheimer disease (AD). Noncoding microRNAs (miRNA) regulate gene expression by degrading messages or inhibiting translation. Using BMC as a paradigm for the study of systemic alterations in AD, we investigated whether peripheral miRNA expression is altered in this condition. MicroRNA levels were assessed using the microRNA microarray (MMChip) containing 462 human miRNA, and the results validated by real time PCR. Sixteen AD patients and sixteen normal elderly controls (NEC) were matched for ethnicity, age, gender and education. The expression of several BMC miRNAs was found to increase in AD relative to NEC levels, and may differ between AD subjects bearing one or two APOE4 alleles. As compared to NEC, miRNAs significantly upregulated in AD subjects and confirmed by qPCR were miR-34a and 181b. Predicted target genes downregulated in Alzheimer BMC that correlated with the upregulated miRNAs were largely represented in the functional categories of Transcription/Translation and Synaptic Activity. Several miRNAs targeting the same genes were within the functional category of Injury response/Redox homeostasis. Taken together, induction of microRNA expression in BMC may contribute to the aberrant systemic decline in mRNA levels in sporadic AD.
Highlights
MicroRNA are noncoding small RNA that bind target sites either in the 3′ untranslated region (UTR) of mRNA to inhibit translation or at the coding regions to degrade the messages (Lee et al 1993; Ruvkun et al 2004; Ambros, 2004; Lim et al 2005)
The study consisted of 16 normal elderly controls (NEC) and 16 Alzheimer disease (AD) miRNA expression profiles, analyzed in four independent experimental blocks with equal numbers of women and men
We made a stringent sample selection based on: (1) well-ascertained cases and controls matched for ethnicity, gender and age and (2) excellent total RNA quality and yield of purified microRNA for the screening of 462 currently-known human microRNA species
Summary
MicroRNA are noncoding small RNA that bind target sites either in the 3′ untranslated region (UTR) of mRNA to inhibit translation or at the coding regions to degrade the messages (Lee et al 1993; Ruvkun et al 2004; Ambros, 2004; Lim et al 2005). Mature microRNAs (miRNA) are approximately 22 nucleotides in length and are expressed under the control of an RNA polymerase II promoter. Loss-of-function mutations have greatly facilitated elucidation of the biological functions of miRNA (Ambros, 2004) including their roles in development, cell differentiation (Ambros, 2004; Ouellet et al 2006), lifespan (Boehm and Slack, 2005) and in diseases such as cancer (Hammond, 2006) and neurodegeneration (Bilen et al 2006a). Neural tissues are believed to manifest the most complex and specific miRNA expression patterns relative to other organs (Babak et al 2004; Strauss et al 2006). The etiology of sporadic AD is likely multifactorial, with carriage of the apolipoprotein E ε4 (APOE4) allele constituting a strong risk factor for the development of this condition (Kamboh, 2004)
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