microRNA-Based Biomarkers and the Diagnosis of Alzheimer’s Disease

microRNA (miRNA)-Mediated Pathogenetic Signaling in Alzheimer’s Disease (AD)

“…Generally characterized as a progressive and enigmatic age-related neurodegeneration, AD involves the progressive mis-regulation of multiple neurobiological pathways at multiple molecular, genetic, epigenetic, neurophysiological, behavioral, mnemonic and cognitive levels. As fore-mentioned, recent data from the literature indicate that microRNA profiling studies in AD suffer from poor consensus which is an acknowledged concern in the field, and this constitutes one of the major current technical challenges in global miRNA abundance and speciation analysis in neurological health and disease [12,13,38]. As has been previously pointed out, the remarkable heterogeneity of AD, extremely variable onset and epidemiology, relatively small sampling sizes in miRNA speciation and complexity studies, and expanding numbers of our aging population acquiring AD brings into question the utility of single miRNA species as being diagnostically useful biomarkers for AD across all stages of this insidious and ultimately fatal human brain disorder.…”

“…Few terminal neurological disorders of the human CNS present with the complexity, heterogeneity, hypervariability and insidiousness of AD [8][9][10][11][12]. Generally characterized as a progressive and enigmatic age-related neurodegeneration, AD involves the progressive mis-regulation of multiple neurobiological pathways at multiple molecular, genetic, epigenetic, neurophysiological, behavioral, mnemonic and cognitive levels.…”

“…Indeed, few places in all of human genome biology are there so high an informationdense network of epigenetic regulatory control as in the CNS family of miRNAs [15][16][17][18][19]. Further to this idea, direct RNA-sequencing-, RT-PCR-, Northern dot blot and miRNA array-based analyses indicate that high abundance miRNAs in the human CNS probably number less than about *45 different miRNA species, and remarkably, only a smaller fraction of these appear to be progressively altered in abundance in AD affected tissues [12][13][14][15][16]. Importantly it appears that the abundance, speciation and complexity of these highly selected miRNAs may vary amongst different human populations in aging, health and neurological disease [11][12][13][14][15].…”

“…Further to this idea, direct RNA-sequencing-, RT-PCR-, Northern dot blot and miRNA array-based analyses indicate that high abundance miRNAs in the human CNS probably number less than about *45 different miRNA species, and remarkably, only a smaller fraction of these appear to be progressively altered in abundance in AD affected tissues [12][13][14][15][16]. Importantly it appears that the abundance, speciation and complexity of these highly selected miRNAs may vary amongst different human populations in aging, health and neurological disease [11][12][13][14][15]. A number of very recent and excellent papers concerning the altered miRNA abundance, speciation and complexity in AD and the aging CNS have recently appeared in the literature and will not be dealt with further here, but interested readers are encouraged to refer to these very recent reports and their content and interpretation [12][13][14][15][16][17][18][19][20].…”

“…Elementary biophysical and ribonucleic acid sequence analysis indicates that a 'typical' 22 nt single-stranded ncRNA (1) because of its polyphosphate backbone assumes the shape of a relatively rigid 'negatively charged rod' in neutral pH solutions with additional topological features characterized in part by that miRNA's unique ribonucleotide sequence; and (2) because miRNAs are composed of 4 different ribonucleotides (adenine, guanine, cytosine and uridine; A,G,C,U) a 22 nt miRNA may assume just over *10 13 possible unique sequence combinations [11][12][13][14][15]. As there are typically so far identified only about 2 9 10 3 different mature miRNAs in humans suggest an extremely high evolutionary selection pressure to utilize only specific ribonucleotide sequences that will yield biologically productive miRNAmRNA interactions [12][13][14][15]. Indeed, few places in all of human genome biology are there so high an informationdense network of epigenetic regulatory control as in the CNS family of miRNAs [15][16][17][18][19].…”