RNA Interference as a Mechanism in Alzheimer's Disease
It presently costs little to assess the transcriptomic state of a cell, the amounts and sequences of various RNA transcripts produced from DNA. Thus a fair amount of research into health, disease, and cell biochemistry is focused on this complex layer of cell behavior. It is comparatively easy to produce a great deal of data and identify differences between cells and cell states, but challenging to connect that to other mechanisms and higher level causes and consequences. The research here illustrates this point, in that the researchers can discuss changes in RNA transcripts observed in Alzheimer's disease, but do not discuss how this work might connect to, say, immune dysregulation or protein aggregation viewpoints of Alzheimer's disease - as it would be hard to make those connections.
A new study shows that RNA interference may play a key role in Alzheimer's. For the first time, scientists have identified short strands of toxic RNAs that contribute to brain cell death and DNA damage in Alzheimer's and aged brains. Short strands of protective RNAs are decreased during aging which may allow Alzheimer's to develop.
In addition to long coding RNAs in cells, there are large numbers of short RNAs (sRNAs) which do not code for proteins. They have other critical functions in the cell. One class of such sRNAs suppresses long coding RNAs through a process called RNA interference that results in the silencing of the proteins that the long RNAs code for. Researchers have now identified very short sequences present in some of these sRNAs that when present can kill cells by blocking production of proteins required for cells to survive. The data suggests that these toxic sRNAs are involved in the death of neurons which contributes to the development of Alzheimer's disease.
The toxic sRNAs are normally inhibited by protective sRNAs. One type of sRNA is called microRNAs. While microRNAs play multiple important regulatory roles in cells, they are also the main species of protective sRNAs. They are the equivalent of guards that prevent the toxic sRNAs from entering the cellular machinery that executes RNA interference. But the guards' numbers decrease with aging, thus allowing the toxic sRNAs to damage the cells. Adding back protective microRNAs partially protects brain cells engineered to produce less protective sRNAs from cell death induced by amyloid beta fragments (which trigger Alzheimer's). Enhancing the activity of the protein that increases the amount of protective microRNAs partially inhibits cell death of brain cells induced by amyloid beta fragments and completely blocks DNA damage (also seen in Alzheimer's patients).