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A 3d illustration of a neuron cell network. (koto_feja/Getty Images)
Toxic strands of RNA known to cause cells to self-destruct have been found in both Alzheimer's and aging brains, suggesting a new approach to treating neurodegenerative diseases such as dementia.
In a study based on mice and human brains led by Northwestern University in the US, researchers identified short lengths of RNA (ribonucleic acid) associated with DNA damage and cell death in relation to the disease and associated factors.
They also found protective short RNA strands in the brain diminish with age, which could allow Alzheimer's to progress, and that people over 80 years old with superior memory – known as 'superagers' – have higher levels of protective short RNAs.
"We found that in aging brain cells, the balance between toxic and protective short RNAs shifts toward toxic ones," says senior author of the study, biochemist Marcus Peter from Northwestern University.
About one in nine US adults over 65 has Alzheimer's, a disease characterized by the development of amyloid-beta plaques, tau tangles, and brain cell death. The chain of events that lead to the excessive death and dysregulation of brain cells has been challenging to identify.
While there are medications that can slow the progress of Alzheimer's disease, the search for more effective options continues. The study authors think targeting RNA strands will open new treatment pathways.
"The overwhelming investment in Alzheimer's drug discovery has been focused on two mechanisms," Peter explains, "reducing amyloid plaque load in the brain – which is the hallmark of Alzheimer's diagnosis and 70 to 80 percent of the effort – and preventing tau phosphorylation or tangles."
Peter and colleagues examined RNA behavior using various methods, including mouse models of Alzheimer's disease, mouse brains, the brains of 'superagers', neurons isolated from healthy and Alzheimer's patients' stem cells, and human brain-derived cell lines.
RNA carries genetic information from DNA to parts of our cells that can translate the genetic recipe and produce proteins that are essential for various cellular functions. Noncoding short RNAs play a role in regulating gene expression by controlling proteins coded for by long-strand RNAs, via a mechanism called RNA interference.
However, RNA's protective effects can deteriorate and even become harmful with age.
The team found that short RNA molecules with specific characteristics can cause cell death. These toxic short RNAs can prevent essential protein production, leading to Death Induced by Survival Gene Elimination (DISE), a process that's active in humans and rodents and plays a key role in killing cancer cells.
Alzheimer's patients have lower cancer rates, which the researchers speculated could mean an overly active DISE mechanism is also contributing to cell death in Alzheimer's.
They found a correlation between DISE, DNA damage, and neuron cell death in Alzheimer's and aging. Neurons in Alzheimer's mouse models, and cells derived from Alzheimer's patients had reduced levels of specific protective short RNA molecules.
The aging brain also has fewer protective RNA molecules, allowing more toxic short RNAs to invade and carry out RNA interference, while superagers have higher levels.
Experiments on cells exposed to amyloid beta fragments in the lab showed that cell death and DNA damage increased, associated with toxic RNA changes.
Increasing the amount of protective RNAs and boosting the activity of the protein responsible seems to protect amyloid beta-exposed cells to some extent, and completely prevents DNA damage, which is also observed in Alzheimer's patients.
Based on these findings, increasing brain levels of protective RNA may be a new strategy for the treatment of neurodegeneration.
"Our data provide a new explanation for why, in almost all neurodegenerative diseases, affected individuals have decades of symptom free life and then the disease starts to set in gradually as cells lose their protection with age," Peter says.
"Stabilizing or increasing the amount of protective short RNAs in the brain could be an entirely new approach to halt or delay Alzheimer's or neurodegeneration in general."
The research has been published in Nature Communications.
