Role of microRNA (miRNA) and Viroids in Lethal Diseases of Plants and Animals. Potential Contribution to Human Neurodegenerative Disorders.

Both plants and animals have adopted a common strategy of using ~18-25-nucleotide small non-coding RNAs (sncRNAs), known as microRNAs (miRNAs), to transmit DNA-based epigenetic information. miRNAs (i) shape the total transcriptional output of individual cells; (ii) regulate and fine-tune gene expression profiles of cell clusters, and (iii) modulate cell phenotype in response to environmental stimuli and stressors. These miRNAs, the smallest known carriers of gene-encoded post-transcriptional regulatory information, not only regulate cellular function in healthy cells but also act as important mediators in the development of plant and animal diseases. Plants possess their own specific miRNAs; at least 32 plant species have been found to carry infectious sncRNAs called viroids, whose mechanisms of generation and functions are strikingly similar to those of miRNAs. This review highlights recent remarkable and sometimes controversial findings in miRNA signaling in plants and animals. Special attention is given to the intriguing possibility that dietary miRNAs and/or sncRNAs can function as mobile epigenetic and/or evolutionary linkers between different species and contribute to both intra- and interkingdom signaling. Wherever possible, emphasis has been placed on the relevance of these miRNAs to the development of human neurodegenerative diseases, such as Alzheimer's disease. Based on the current available data, we suggest that such xeno-miRNAs may (i) contribute to the beneficial properties of medicinal plants, (ii) contribute to the negative properties of disease-causing or poisonous plants, and (iii) provide cross-species communication between kingdoms of living organisms involving multiple epigenetic and/or potentially pathogenic mechanisms associated with the onset and pathogenesis of various diseases.

Systemic Inflammation in C57BL/6J Mice Receiving Dietary Aluminum Sulfate; Up-Regulation of the Pro-Inflammatory Cytokines IL-6 and TNFα, C-Reactive Protein (CRP) and miRNA-146a in Blood Serum.

A number of experimental investigations utilizing different murine species have previously reported: (i) that standard mouse-diets supplemented with physiologically realistic amounts of neurotoxic metal salts substantially induce pro-inflammatory signaling in a number of murine tissues; (ii) that these diet-stimulated changes may contribute to a systemic inflammation (SI), a potential precursor to neurodegenerative events in both the central and the peripheral nervous system (CNS, PNS); and (iii) that these events may ultimately contribute to a chronic and progressive inflammatory neurodegeneration, such as that which is observed in Alzheimer's disease (AD) brain. In these experiments we assayed for markers of SI in the blood serum of C57BL/6J mice after 0, 1, 3 and 5 months of exposure to a standard mouse diet that included aluminum-sulfate in the food and drinking water, compared to age-matched controls receiving magnesium-sulfate or no additions. The data indicate that the SI markers that include the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), the acute phase reactive protein C-reactive protein (CRP) production and a triad of pro-inflammatory microRNAs (miRNA-9, miRNA-125b and miRNA-146a) all increase in the serum after aluminum-sulfate exposure. For the first time these results suggest that ad libitum exposure to aluminum-sulfate at physiologically realistic concentrations, as would be found in the human diet over the long term, may predispose to SI and the potential development of chronic, progressive, inflammatory neurodegeneration with downstream pathogenic consequences.

Aluminum, the genetic apparatus of the human CNS and Alzheimer's disease (AD).

The genomes of eukaryotes orchestrate their expression to ensure an effective, homeostatic and functional gene signaling program, and this includes fundamentally altered patterns of transcription during aging, development, differentiation and disease. These actions constitute an extremely complex and intricate process as genetic operations such as transcription involve the very rapid translocation and polymerization of ribonucleotides using RNA polymerases, accessory transcription protein complexes and other interrelated chromatin proteins and genetic factors. As both free ribonucleotides and polymerized single-stranded RNA chains, ribonucleotides are highly charged with phosphate, and this genetic system is extremely vulnerable to disruption by a large number of electrostatic forces, and primarily by cationic metals such as aluminum. Aluminum has been shown by independent researchers to be particularly genotoxic to the genetic apparatus, and it has become reasonably clear that aluminum disturbs genetic signaling programs in the CNS that bear a surprising resemblance to those observed in Alzheimer's disease (AD) brain. This paper will focus on a discussion of two molecular-genetic aspects of aluminum genotoxicity: (1) the observation that micro-RNA (miRNA)-mediated global gene expression patterns in aluminum-treated transgenic animal models of AD (Tg-AD) strongly resemble those found in AD; and (2) the concept of "human biochemical individuality" and the hypothesis that individuals with certain gene expression patterns may be especially sensitive and perhaps predisposed to aluminum genotoxicity.

Progressive inflammatory pathology in the retina of aluminum-fed 5xFAD transgenic mice.

At least 57 murine transgenic models for Alzheimer's disease (Tg-AD) have been developed to overexpress the 42 amino acid amyloid-beta (Aß42) peptide in the central nervous system (CNS). These 'humanized murine Tg-AD models' have greatly expanded our understanding of the contribution of Aß42 peptide-mediated pro-inflammatory neuropathology to the AD process. A number of independent laboratories using different amyloid-overexpressing Tg-AD models have shown that supplementation of murine Tg-AD diets and/or drinking water with aluminum significantly enhances Aß42 peptide-mediated inflammatory pathology and AD-type cognitive change compared to animals receiving control diets. In humans AD-type pathology appears to originate in the limbic system and progressively spreads into primary processing and sensory regions such as the retina. In these studies, for the first time, we assess the propagation of Aß42 and inflammatory signals into the retina of 5xFAD Tg-AD amyloid-overexpressing mice whose diets were supplemented with aluminum. The two most interesting findings were (1) that similar to other Tg-AD models, there was a significantly accelerated development of Aß42 and inflammatory pathology in 5xFAD Tg-AD mice fed aluminum; and (2) in aluminum-supplemented animals, markers for inflammatory pathology appeared in both the brain and the retina as evidenced by an evolving presence of Aß42 peptides, and accompanied by inflammatory markers - cyclooxygenase-2 (COX-2) and C-reactive protein (CRP). The results indicate that in the 5xFAD Tg-AD model aluminum not only enhances an Aß42-mediated inflammatory degeneration of the brain but also appears to induce AD-type pathology in an anatomically-linked primary sensory area that involves vision.

Upregulation of micro RNA-146a (miRNA-146a), a marker for inflammatory neurodegeneration, in sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Straussler-Scheinker (GSS) syndrome.

A mouse- and human-brain-abundant, nuclear factor (NF)-кB-regulated, micro RNA-146a (miRNA-146a) is an important modulator of the innate immune response and inflammatory signaling in specific immunological and brain cell types. Levels of miRNA-146a are induced in human brain cells challenged with at least five different species of single- or double-stranded DNA or RNA neurotrophic viruses, suggesting a broad role for miRNA-146a in the brain's innate immune response and antiviral immunity. Upregulated miRNA-146a is also observed in pro-inflammatory cytokine-, Aß42 peptide- and neurotoxic metal-induced, oxidatively stressed human neuronal-glial primary cell cocultures, in murine scrapie and in Alzheimer's disease (AD) brain. In AD, miRNA-146a levels are found to progressively increase with disease severity and co-localize to brain regions enriched in inflammatory neuropathology. This study provides evidence of upregulation of miRNA-146a in extremely rare (incidence 1-10 per 100 million) human prion-based neurodegenerative disorders, including sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Straussler-Scheinker syndrome (GSS). The findings suggest that an upregulated miRNA-146a may be integral to innate immune or inflammatory brain cell responses in prion-mediated infections and to progressive and irreversible neurodegeneration of both the murine and human brain.

Micro RNA-125b (miRNA-125b) function in astrogliosis and glial cell proliferation.

Micro RNAs (miRNAs) are post-transcriptional modulators of gene expression that regulate the stability and translation of their target messenger RNAs (mRNAs). Here we report that the levels of a human brain-enriched miRNA-125b are up-regulated in interleukin-6 (IL-6)-stressed normal human astrocytes (NHA), a treatment known to induce astrogliosis. In vitro, anti-miRNA-125b added exogenously to IL-6-stressed NHA cultures attenuated both glial cell proliferation and increased the expression of the cyclin-dependent kinase inhibitor 2A (CDKN2A), a miRNA-125b target and negative regulator of cell growth. A strong positive correlation between miRNA-125b abundance and the glial cell markers glial fibrillary acidic protein (GFAP) and vimentin, and CDKN2A down-regulation was noted in advanced Alzheimer's disease (AD) and in Down's syndrome (DS) brain, chronic neurological disorders associated with astrogliosis. The results suggest that miRNA-125b up-regulation contributes to astrogliosis and to defects in the cell cycle that are characteristic of degenerating brain tissues.