Breakthrough in Dementia Treatment-Microrna-34c, Research Paper Example

Dementia has plagued the human race for centuries.  According to World Health Organization reports some 36.6 million people were affected by dementia in 2010. Further, reports are that the prevalence has increased greatly with age. 5% of people over age 65 are likely to develop the abnormality; 20-40% of people between the ages of 64-85 are most likely to experience this memory dysfunction. Rates are slightly higher in women over 65 year old than men (Sadock et.al, 2006).

Dementia is characteristic of a number of other disorders affecting cognition. These include Alzheimer’s disease, vascular, frontotemporal, semantic and Lewy bodies’ dementia each type emerging from the specific part of brain function affected. Typical symptoms are memory dysfunction; attention disruptions; language expression and problem solving difficulties. Just 10% of cases are classified reversible. Therefore, treatment is limited to addressing further loss of memory and helping patients and family members function with the dysfunction (Sadock et.al, 2006).

RNA interference (RNAi) is usually referred to as post transcriptional gene silencing (PTGS).The biological process encompasses RNA molecules inhibiting gene expression by destroying certain types of mRNA molecules. When encoded by eukaryotic nuclear DNA, miRNAs translate adapting a base-pairing mechanism complementing sequences within mRNA molecules. Gene silencing occurs initiated by translational repression or target degradation (Chen & Rajewsky, 2007). Researchers, Zovoilis (2011) and counterparts have made a startling breakthrough in associating microRNA-34c with dementia treatment.

Experiment: miRNAs enrichment in the hippocampus of mice

Zovoilis (2011) and his team used massive parallel sequencing in a detailed exploration of unprecedented levels to complete and absolute digitized mouse hippocampal miRNAome. Prior to their experiment they realized that MicroRNAs were key regulators of transcriptome plasticity subsequently implicated in pathogenesis of brain diseases. By utilizing integrative genetics, researchers identified miR-34c as a negative constraint of memory consolidation. Further they revealed through experiments that miR-34c levels are elevated in the hippocampus of AD patients, which corresponded with mouse models experimented upon (Zovoilis et.al, 2011)

Coinciding with these realities researchers then experimented with targeting miR-34 seed rescues learning ability in these mouse models. Data retrieved from experiments was highly suggestive that’ miR-34c could be a marker for the onset of cognitive disturbances linked to AD and indicate that targeting miR-34c could be a suitable therapy’ (Zovoilis et.al, 2011, pp 4299). There after the aim was to reveal miRNAs enriched in mouse hippocampus. Unto the time of their experiment this phenomenon was unidentified (Zovoilis et.al, 2011).

They believed that by exploring alternative technologies which were significant to hippocampal age related memory function and pathogenesis, a discovery could be made. This could be beneficial to the science. In the process they realized that miR-34c is implicated with the pathogenesis of cognitive decline. This was observed though combining molecular and behavioural experimental approaches. These alternative experimental techniques revealed that miR-34c is essentials for efficient memory function. Precisely, researchers concluded that this data was enough in indicating by targeting miR-34c memory impairment in people affected with dementia is useful (Zovoilis et.al, 2011).

Actual results show where ‘massive parallel sequencing of small RNA libraries reveals the hippocampal miRNAome. (A) Contribution (in percent) of miRNAs to the total number of small non-coding RNAs in the range of 18–26 nt detected by sequencing. (B) Proportion of detected mature miRNAs, regarding the total number of known genes and miRNAs in miRBase. (C) Right panel: Distribution of miRNAs to different classes based to their sequence counts and contribution of each of these miRNA classes to the total miRNA sequence count. Left panel: Proportion of sequence counts per miRNA with respect to the total number of counts attributed to miRNAs in hippocampus. (D) Sequence counts of top ranking hippocampal miRNAs relative to the respective counts in whole brain (Zovoilis et.al, 2011, pp 4300).

The Truth Clarified: High miR-34c levels are linked to pathogenesis of learning impairment.

Zovoilis (2011) and his team later investigated whether miR-34c influences memory impairment. As such, they measured miR-34c levels in the hippocampus of 24-month-old mice. This was compared to a model for age-associated memory impairment, in APPPS1-21 mice. Hippocampal miR-34c showed significant upregulatation in hippocampal in two mouse models. A correlation was further established with memory function. Also among confirmed targets of the miR-34 family is Sirt1 mRNA which binds miR-34c sites (Zovoilis et.al, 2011).

It was further discovered that targeting of Sirt1 mRNA by miR-34c applied to neuronal cells as well. The relationship between hippocampal SIRT1 and memory function in mice ignited the reasoning that by measuring SIRT1 levels would be a suitable read out of miR-34c in vivo activity. When applying a fear conditioning mechanism learning-induced changes in SIRT1 protein levels revealed inverted correlation with the regulation of miR-34c 3.

In assessing a model of amyloid pathology connected to AD, researchers asked the question ‘whether inhibition of miR-34c seed would affect memory function in a mouse model for neurodegeneration’ (Zovoilis et.al, 2011, pp 4301). It was observed that hippocampal miR-34c demonstrated significant upregulatation between the two mouse models. Interestingly, this correlated with impaired memory function (Zovoilis et.al, 2011).

The Breakthrough: Targeting miR-34c seed rescues learning impairment

Three experiments embracing three control groups led to this breakthrough announced by scientists. The purpose was testing therapeutic potential of targeting mir-34c signaling. Complete and absolute digitized quantification of the mouse hippocampal miRNAome was evaluated. miR-34c was found to be upregulated in AD patients after qPCR analysis measured miR-34c levels in post-mortem tissue samples with age-matched controls. (A) miR-34c levels (qPCR) were elevated in the hippocampus (*P¼0.05) of human AD patients (n¼6; 4females, 2 males) when compared with age-matched controls (n¼8, 2 females, 6 males). Braack & Braack stage VI was diagnosed in 5 cases and one stage V.  There was no significant age difference observed in (B) or post-mortem delay in (C) (Zovoilis et.al, 2011).

The second experiment focused on memory testing applying integrative genomics among the three groups A, B and C. High levels of miR-34c were implicated with memory impairment. Group (A) showed in ther left panel administration of miR-34c mimic and the respective scramble miR; right panel revealed elevated hippocampal miR-34c levels after miR-34c mimic administration. Control (B) impaired learning in 3-month-old wild-type mice with high level of miR-34c after treatment with the miRNA mimic in the upper panel while control (C) Hippocampal SIRT1 levels correlate with miR-34c expression (Zovoilis et.al, 2011, pp 4303).

Thirdly, researchers focused on binding influences of miR-34c to SIRT1 30UTR. It was discovered that when applied to (A) protectors prevent miR34c mimic from binding to the Sirt1 mRNA. In control (B) reveled where co-injection with the miR-34c-Sirt1 protector rescued learning impairment (n¼8, 8; *P¼0.04). (C) showed where target protector negative control emerged in SIRT1 protein (left) and mRNA levels (right) treated mice (Zovoilis et.al, 2011, pp 4304).

Implications based on what was known previously

Scientists have struggled for centuries finding treatment much more cures for dementia. The etiology of dementia is diverse and could influence effective response to treatment. While microRNA-34c is highlighted as a novel target to treat dementias; in this study an obvious limitation is that different types of dementias were not classified in application of the treatment. We still do not know which type of dementia microRNA-34c can successfully resolve. Hence, immediate application of these findings from this study must be further evaluated for its efficacy across types of dementia existent in the science (Raina et.al, 2008). Hence, further intense research is mandatory.

Works cited

Raina P, Santaguida P, Ismaila A. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Annals of Internal Medicine vol 148, 5; pp 379–97 2008. Print

Sadock, Benjamin, Sadock, James., Alcott  Virginia. Kaplan & Sadock’s. Concise textbook of clinical psychiatry. 2008. Print.

Zovoilis, A. Agbemenyah, H. Agis-Balboa, R. Stilling, R. Edbauer, D. Rao, P. Farinelli,L.

Delalle, Schmitt, Falkai, P. Bahari-Javan, S. Burkhardt, S. Sananbenesi, F., & Fischer, A. microRNA-34c is a novel target to treat dementias. The EMBO Journal vol, 30, 4299–4308. 2011.Print

Chen, Kevin; Rajewsky, Nikolaus. The evolution of gene regulation by transcription factors and microRNAs. Nature Reviews Genetics  Vol 8, No 2; pp 93–103. 2007. Print