Large numbers of nerve cells die in the brains of patients with Alzheimer’s dementia. This can have various triggers. Researchers have now discovered a new culprit: short RNA sequences (sRNA), which have a toxic effect on neurons. At the same time, sRNAs with protective effects are less common in older brains and in Alzheimer’s disease, the study showed. Accordingly, an imbalance of these two types of sRNA molecules could be responsible for the death of neurons. The finding helps to better understand the disease and opens up new possibilities for drugs against neurodegenerative diseases.
Alzheimer’s is one of the most common neurodegenerative diseases and the most common form of dementia in old age. In Germany, around 1.8 million people live with dementia, more than two thirds of whom have Alzheimer’s. Among other things, patients suffer from memory loss because excessive numbers of nerve cells in their brain die. This can happen as a result of clumping of so-called amyloid beta or tau proteins, but it can also have other reasons. How exactly neuron cell death occurs has so far been poorly researched.
Interaction between two RNA groups
A team led by Bidur Paudel from Northwestern University in the USA has now searched for the underlying mechanism for neuron death at the molecular level. To do this, the neuroscientists examined the brains of laboratory mice that had Alzheimer’s disease as well as old and young healthy mice. They also analyzed the brains of deceased so-called super-agers – people over 80 years old whose memory performance corresponds to that of a younger person between 50 and 60 years old. In addition, the researchers also examined neurons in cell cultures that had developed from stem cells from young and old healthy people as well as from Alzheimer’s patients. In addition, they cultured neuron-like cells from human brains in the laboratory and treated them with amyloid beta fragments to simulate Alzheimer’s disease. In all of these models, the scientists looked for molecules that appear in Alzheimer’s conditions but not in healthy people or mice.
The analyzes showed that certain RNA molecules occur more frequently in the brains of older individuals as well as mice and humans with Alzheimer’s disease. Unlike the comparatively large molecules of messenger RNA (mRNA), these short RNA sequences (sRNA) do not code for proteins, but rather have regulatory tasks in the cell. However, some of these sRNA had a toxic effect in the experiments, damaged the DNA, hindered the formation of vital proteins and caused the neurons to die, as the researchers report. At the same time, another group of sRNA molecules was less present in older individuals: short RNA sequences that protect against precisely these toxic sRNAs. “We found that in aging brain cells, the balance between toxic and protective sRNAs shifts toward toxic,” says senior author Marcus Peter from Northwestern University.
The team concludes that the altered interaction between these two RNA groups could promote the development of Alzheimer’s disease. The brains of super-agers also had unusually high levels of this protective sRNA, the studies further revealed. As a result, they appear to be better protected against nerve death and have better memory than their peers, Paudel and his colleagues suspect.
Opportunity for new therapeutic approaches against Alzheimer’s and Co
The researchers explain that it is the first time that Alzheimer’s disease has been linked to RNA molecules. The findings could now help to better understand and treat the disease and other neurodegenerative diseases such as Parkinson’s, Huntington’s and ALS. “Our data provide a new explanation for why the people affected in almost all neurodegenerative diseases live a symptom-free life for decades and then the disease sets in gradually: because the cells lose their protection as they get older,” explains Peter.
So far, doctors have tried to help those affected primarily by combating the harmful protein deposits in their brains. However, so far with moderate success. In the future, researchers could instead focus on developing drugs against neurodegenerative diseases that promote protective RNA molecules or inhibit toxic RNA, Paudel and his colleagues suggest. Substances with such an effect already exist, as the team discovered in follow-up experiments. However, these must first be further tested and improved in order to be used effectively and safely, says Peter.
The researchers now want to devote themselves to this task. It is important to generate a balance of toxic and protective sRNAs, because the toxic sRNAs also have a naturally useful function: they kill cancer cells. This may also be the reason why Alzheimer’s patients are less likely to develop cancer.
Source: Bidur Paudel (Northwestern University) et al., Nature Communications, doi: 10.1038/s41467-023-44465-8