RNA interference and its role in Alzheimer’s disease

Scientists from Northwestern Medicine have demonstrated that RNA interference could have a crucial role in the onset and development of Alzheimer’s disease (AD). For the first time, researchers have identified short strands of toxic RNAs that contribute to brain cell death and DNA damage in Alzheimer’s and aged brains, and that during ageing, short strands of protective RNAs decrease.

The study¹ also revealed that individuals known as ‘SuperAgers’, those aged 80 and older with a superior memory capacity to that of individuals 20 to 30 years younger, have a higher amount of protective short RNA strands in their brain cells.

Corresponding study author Dr Marcus Peter, Tom D Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine, stated: “Nobody has ever connected the activities of RNAs to Alzheimer’s…We found that in ageing brain cells, the balance between toxic and protective sRNAs (short RNAs) shifts toward toxic ones.”

Alzheimer’s disease

Alzheimer’s is the most common cause of dementia. Molecular pathogenesis of the hallmarks of the disease include plaques, composed of amyloid β (Aβ), and tangles, composed of hyperphosphorylated tau.²  

Although familial AD is a very rare autosomal dominant disease with early onset, sporadic AD is very common, with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors.³

Dr Peter explained: “The overwhelming investment in Alzheimer’s drug discovery has been focused on two mechanisms: 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…However, treatments aimed at reducing amyloid plaques have not yet resulted in an effective treatment that is well tolerated.”

sRNAs

Cellular functions rely on numerous protein-coding and noncoding RNAs and the RNA-binding proteins associated with them, which form ribonucleoprotein complexes (RNPs).⁴ Short RNAs (sRNAs) do not code for proteins. One class of sRNAs suppress long coding RNAs through RNA interference, which results in the silencing of the proteins long RNAs code for.

The team found very short sequences present in some of these sRNAs. These can kill cells by blocking the production of proteins required for cells to survive. Their data indicated that the toxic sRNAs are involved in the death of neurons, which contributes to the development of AD.

Normally, the toxic sRNAs are inhibited by protective sRNAs, such as microRNAs. These have numerous important regulatory roles in cells and are the main species of protective sRNAs. However, their numbers decrease with ageing which allows the toxic sRNAs to damage cells.

Studying brains

The scientists analysed the brains of AD mouse models, the brains of young and old mice, and induced pluripotent stem cell (IPSC)-derived neurons from both young and aged individuals, including from AD patients. In addition, they analysed the brains of the ‘SuperAgers’ and multiple human brain-derived neuron-like cell lines treated with amyloid beta fragments, which is a trigger of AD.

The team observed that brain cells that were engineered to produce fewer sRNAs were partially protected from cell death induced by amyloid beta fragments by adding back protective miRNAs. Also, enhancing the activity of the protein that increases the amount of protective miRNAs partially inhibited cell death of brain cells induced by amyloid beta fragments, completely blocking DNA damage. This was also seen in AD patients.

Further applications

This discovery could be relevant beyond AD, as Dr Peter elucidates: “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.”

The team aims to determine the exact contribution of toxic sRNAs to cell death seen in the disease in different animal and cellular models, as well as in the brains of AD patients. This will enable them to screen for better compounds that would selectively increase the level of protective sRNAs or block the action of the toxic ones.

“Our data supports the idea that stabilising 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.” Although such drugs exist, he continued, they would need to be tested in animal models and improved.

This study was published in Nature Communications.

References

¹ Paudel B, Jeong SY, Martinez CP, et al. Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer’s disease and aging. Nat Communications. 15, 264 (2024). Available from: https://doi.org/10.1038/s41467-023-44465-8

² Blennow K, Leon MJ, Zetterberg H. Alzheimer’s disease. The Lancet. 2006 July 29 [2024 January 18]; 368(9533):387-403. Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140673606691137/fulltext

³ Blennow K, Leon MJ, Zetterberg H. Alzheimer’s disease. The Lancet. 2006 July 29 [2024 January 18]; 368(9533):387-403. Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140673606691137/fulltext

⁴ Cooper TA, Dreyfuss G, Wan L. RNA and Disease. Cell. 2009 February 20 [2024 January 18]; 136(4):777-793. Available from: https://www.cell.com/fulltext/S0092-8674(09)00148-2