Data Mining - Concepts and Techniques.

The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.

https://science.sciencemag.org/content/sci/261/5123/921.full.pdf

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

MicroRNAs (miRNAs) are a large family of post-transcriptional regulators of gene expression that are ~21 nucleotides in length and control many developmental and cellular processes in eukaryotic organisms. Research during the past decade has identified major factors participating in miRNA biogenesis and has established basic principles of miRNA function. More recently, it has become apparent that miRNA regulators themselves are subject to sophisticated control. Many reports over the past few years have reported the regulation of miRNA metabolism and function by a range of mechanisms involving numerous protein-protein and protein-RNA interactions. Such regulation has an important role in the context-specific functions of miRNAs.

http://m.docente.unife.it/franco.pagani/lezione-1101a-mirna/articoli-smallrna/2010%20FIlipowic%20The%20widespread%20regulation%20of%20miRNA%20%20copy.pdf

The widespread regulation of microRNA biogenesis, function and decay.

Some cases of Alzheimer's disease are inherited as an autosomal dominant trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcripts encoded within this region. One of these transcripts (S182) corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease. Because these changes occurred in conserved domains of this gene, and are not present in normal controls, they are likely to be causative of AD3.

Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68880-6.pdf

Mild cognitive impairment

Deficiency in docosahexaenoic acid (DHA), a brain-essential omega-3 fatty acid, is associated with cognitive decline. Here we report that, in cytokine-stressed human neural cells, DHA attenuates amyloid-β (Aβ) secretion, an effect accompanied by the formation of NPD1, a novel, DHA-derived 10,17S-docosatriene. DHA and NPD1 were reduced in Alzheimer disease (AD) hippocampal cornu ammonis region 1, but not in the thalamus or occipital lobes from the same brains. The expression of key enzymes in NPD1 biosynthesis, cytosolic phospholipase A2 and 15-lipoxygenase, was altered in AD hippocampus. NPD1 repressed Aβ42-triggered activation of proinflammatory genes while upregulating the antiapoptotic genes encoding Bcl-2, Bcl-xl, and Bfl-1(A1). Soluble amyloid precursor protein-α stimulated NPD1 biosynthesis from DHA. These results indicate that NPD1 promotes brain cell survival via the induction of antiapoptotic and neuroprotective gene-expression programs that suppress Aβ42-induced neurotoxicity.

/pdf/a-role-for-docosahexaenoic-acid-derived-neuroprotectin-d1-in-d6hza7ngtt.pdf

A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease.

http://www.jbc.org/content/278/44/43807.full.pdf

Novel Docosanoids Inhibit Brain Ischemia-Reperfusion-mediated Leukocyte Infiltration and Pro-inflammatory Gene Expression

http://www.jbc.org/content/278/51/51974.full.pdf

Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. Vol. 278 (2003) 43807–43817

Micro-RNAs constitute a family of small noncoding ribonucleic acids that are posttranscriptional regulators of messenger RNA activity. Although micro-RNAs are known to be dynamically regulated during neural development, the role of micro-RNAs in brain aging and neurodegeneration is not known. This study examined micro-RNA abundance in the hippocampal region of fetal, adult and Alzheimer's disease brain. The data indicate that micro-RNAs encoding miR-9, miR-124a, miR-125b, miR-128, miR-132 and miR-219 are abundantly represented in fetal hippocampus, are differentially regulated in aged brain, and an alteration in specific micro-RNA complexity occurs in Alzheimer hippocampus. These data are consistent with the idea that altered micro-RNA-mediated processing of messenger RNA populations may contribute to atypical mRNA abundance and neural dysfunction in Alzheimer's disease brain.

Micro-RNA speciation in fetal, adult and Alzheimer's disease hippocampus.

Circular RNAs (circRNAs) are a naturally occurring family of noncoding RNAs (ncRNAs) highly represented in the eukaryotic transcriptome. Recently characterized, traditional methods of RNA detection and analysis requiring a free 5′ or 3′ ribonucleotide terminus may have significantly underestimated circRNA abundance and significance in eukaryotic cells (Salzman et al., 2012; Wilusz and Sharp, 2013; unpublished observations). Intrinsically resistant to exonucleolytic RNA decay, circRNAs appear to be enriched in mammalian brain tissues (Hansen et al., 2013; Memczak et al., 2013). Interestingly, specific ncRNAs such as the evolutionary ancient microRNA-7 (miRNA-7; chr 9q21.32; an important post-transcriptional regulator of human brain gene expression), are not only highly abundant in human brain, but are also associated with a circRNA for miRNA-7 (ciRS-7), in the same tissues; ciRS-7 contains multiple, tandem anti-miRNA-7 sequences (Burmistrova et al., 2007; Hansen et al., 2013; Lukiw et al., 2013). ciRS-7 thereby acts as a kind of endogenous, competing, anti-complementary miRNA “sponge” to adsorb, and hence quench, normal miRNA-7 functions. Using Northern blot hybridization techniques and the circularity-sensitive circRNA probe RNaseR we here provide initial evidence of a mis-regulated miRNA-7-circRNA system in the sporadic Alzheimer's disease (AD) hippocampal CA1 region (Figure ​(Figure1).1). Deficits in ciRS-7, and ciRS-7 “sponging activities” might be expected to increase ambient miRNA-7 levels in AD-affected brain cells, as is observed, to ultimately contribute to the down-regulation of selective miRNA-7-sensitive messenger RNA (mRNA) targets (Cogswell et al., 2008; unpublished observations). The presence of up-regulated miRNA-7, due to a deficiency in ciRS-7 “sponging” effects, has high probability to down-regulate AD-relevant targets, such as, for example, the ubiquitin protein ligase A (UBE2A; miRNA-7-UBE2A mRNA energy of association, EA = −22.86 kcal/mol). UBE2A, an autophagic, phagocytic protein essential in the clearance of amyloid peptides in AD and other progressive inflammatory degenerations of the human CNS, is depleted in AD brain (Bingol and Sheng, 2011; Lonskaya et al., 2013). Such miRNA-mRNA regulatory systems mediated by a family of cell- and/or tissue-enriched circRNAs may represent another important layer of epigenetic control over gene expression in health and disease. Indeed, technological advancement and recent discoveries in the field of ncRNAs continue to challenge our basic doctrines of nucleic acid biochemistry and evolutionary biology. Deficits in other circRNA-mediated “miRNA sponging systems” and ambient up-regulation of specific inducible miRNAs may help explain the widely observed, generalized and progressive down-regulation of gene expression that is characteristic of the sporadic AD brain (Loring et al., 2001; Colangelo et al., 2002; Ginsberg et al., 2012; Lukiw, 2013).



Figure 1

(A) Detection of circRNA for miRNA-7 (ciRS-7) in sporadic Alzheimer's disease (AD) and age-matched control hippocampal CA1 [control (C) N = 4; AD (A) N = 6]; the single upper ciRS-7 (~1400 nt) band contains ~70 selectively conserved miRNA-7 binding sites ...

/pdf/circular-rna-circrna-in-alzheimer-s-disease-ad-ahpdtvs6mr.pdf

Walter J. Lukiw

Papers

A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease.

Novel Docosanoids Inhibit Brain Ischemia-Reperfusion-mediated Leukocyte Infiltration and Pro-inflammatory Gene Expression

Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. Vol. 278 (2003) 43807–43817

Micro-RNA speciation in fetal, adult and Alzheimer's disease hippocampus.

Circular RNA (circRNA) in Alzheimer’s disease (AD)