The causes of neuronal degeneration in Alzheimer’s disease remain largely unknown, but hypotheses have mainly focused on abnormal protein metabolisms leading to the formation of the amyloid-β (Aβ) peptide or abnormally phosphorylated tau protein. Recently, new findings have focused the interest on non-coding RNA Citation[1]. These molecules are present in cells and do not originate from protein-coding genes. According to their lengths and functions, they include miRNAs, siRNAs, small RNAs, and medium and large RNAs. Concerning microRNAs, they are mainly regulated at the transcriptional level. The pri-miRNA is the primary miRNA-encoding transcript. The nuclease Drosha can cleave the pri-miRNA in the nucleus to generate a 60–80 nucleotide stem-loop called the pre-miRNA that is actively transferred into the cytoplasm. At this site, the nuclease Dicer associated with other proteins (Argonaut 2, Tar RNA-binding protein [TRBP], protein kinase R activating protein [PACT]) forming the RNA-induced silencing complex (RISC) finalizes the mature miRNA, which can interfere with mRNA targets producing mRNA cleavage or translation inhibition. miRNAs have been implicated in the regulation of cell death Citation[2,3]. It is also interesting to notice that the RISC proteins PACT and TRBP can also interact with the proapoptotic protein PKR, which can block protein translation and has been associated with neuronal degeneration in Alzheimer’s disease Citation[4].
Recent studies have now established that RNAs, beside their roles as mRNAs, could be implicated in various brain and neurological diseases Citation[5]. The fact that miRNAs, through their action on translation modulation, can contribute to the abnormal cellular processes detected in Alzheimer’s disease is now substantiated by several recent findings. In 2006, WJ Lukiw reported a study analyzing several miRNA levels in fetal, adult and Alzheimer’s disease hippocampus Citation[6]. Using Northern analysis, the findings revealed that levels of miR-9, mir-125b and miR-128 were elevated in Alzheimer’s brains compared with aged-matched controls. Mir-124a was reduced in Alzheimer brains, and mir-132 and miR-219 were not modified. However, these results were difficult to interpret, especially in terms of cellular dysfunctions because brain samples were composed of neurons, glial, vascular and other cell types. Consequently, in 2008, three studies have been published to date linking miRNA modifications with the regulation of β-secretase (BACE 1) which cleaves amyloid precursor protein (APP) to form the Aβ peptide. Wang et al. reported that the levels of mir-107 decreased in Alzheimer’s brains compared with aged-matched controls Citation[7]. MiR-26a was not modified in Alzheimer’s brains. In situ hybridization assessment revealed that cerebral cortical laminas, particularly affected by the pathology, had reduced neuronal miR-107 expression. In addition, they found that one physiological miR-107 binding site could be detected on BACE 1 mRNA and that BACE 1 mRNA levels had a tendency to augment as miR-107 levels decreased during the course of the disease. This is the first study associating a key enzyme involved in the production of Aβ peptide, BACE 1 and one miRNA: mir-107. Hebert et al. also reported findings suggesting that miRNA modifications could contribute to BACE 1 expression Citation[8]. The authors found that mir-29a, mir-29b-1 and mir-9 could regulate BACE 1 expression in vitro. In Alzheimer’s brains, miR-29a and miR-29b-1 were significantly decreased in patients with abnormally augmented BACE 1 protein. In addition, the authors found that these two miRNAs can modulate BACE 1 activity and Aβ production in cell cultures. A third study, recently published by Faghihi et al., confirmed the link between BACE 1 and noncoding RNA Citation[9]. Their study demonstrated that BACE 1 mRNA expression is controlled by a noncoding RNA, the BACE 1 natural antisense transcript (BACE 1-AS), which is increased by cell stress such as the exposure to Aβ peptide, creating a feed-forward mechanism for BACE 1 expression and Aβ production.
Altogether, these studies revealed that abnormal levels of miRNAs or other non-coding RNA are present in Alzheimer’s brains and can be implicated in the abnormal regulation of a key enzyme such as BACE 1 at the post-transcriptional level. These results do not eliminate the possibility that other controlling pathways targeting BACE 1 or other proteins might be affected in Alzheimer’s brains.
These findings underline the fact that miRNAs and other non-coding RNAs could represent a new tool as biological markers or a new target for pharmacological approaches.
A recent study has assessed the importance of deregulation of miRNA expression in brains and cerebrospinal fluid (CSF) of Alzheimer’s patients and proposes to use the modifications of these levels as putative biomarkers of the disease Citation[10]. The changes found in patients linked miRNAs anomalies to molecular pathways such as amyloid processing, neurogenesis, insulin resistance and innate immunity. In addition, the authors found an altered expression of miRNA in the CSF of patients affected by Alzheimer’s disease. For example, 60 miRNAs were found significantly different in the CSF of patients between Braak stage 5 and Braak stage 1, which is the neuropathological evaluation of the disease progression. Further analysis will be needed to know if the assessment of CSF miRNAs could complement the current evaluation of Aβ and total and phosphorylated tau protein presently performed in the CSF of patients.
So far, it is difficult to determine if the changes in miRNA expression detected in the brains or CSF of Alzheimer’s patients are primary or secondary events, or both. Nevertheless, it seems plausible to think that, early or late in the evolution of the disease, they could contribute to the pathogenesis of the observed lesions and neuronal loss. It is thus important to determine how new pharmacological interventions could help to modify the detrimental consequences of abnormal miRNA levels in the brains of patients. In 2005, Krutzfeldt et al. published the first report on antagomirs able to silence miRNAs in vivoCitation[11]. Antagomirs are chemically engineered oligonucleotides that are able to silence specific miRNAs in mice. After systemic administration of antagomirs against various miRNAs, the authors reported a marked reduction of corresponding miRNA levels in different organs such as liver, heart, lungs, kidney and muscles. Unfortunately, in a more recent study, the same group showed that antagomirs, when systemically injected, did not silence miRNAs in the mouse CNS but were efficient after local injection into the cerebral cortex Citation[12]. It is interesting to see that the proof-of-concept is good concerning miRNA modification in the brain but further modifications of antagomirs are needed to allow crossing of the BBB.
In conclusion, we are still far away from a real understanding of the biology of miRNAs in the human brain and the reasons for abnormal modifications of miRNAs in the brains of Alzheimer’s patients. miRNAs, through mRNA silencing, can interact with many cellular pathways and can provide new avenues of research to alter the dramatic evolution of cognitive signs detected in affected individuals.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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