Toxic RNAs: The Hidden Cause of Neuron Death in Alzheimer’s Uncovered

Short, toxic RNAs kill brain cells and may allow Alzheimer’s to develop.

• New finding to understand brain cell loss in neurodegenerative disease
• Increasing protective short RNAs may be new approach to halt or delay Alzheimer’sAlzheimer's disease is a disease that attacks the brain, causing a decline in mental ability that worsens over time. It is the most common form of dementia and accounts for 60 to 80 percent of dementia cases. There is no current cure for Alzheimer's disease, but there are medications that can help ease the symptoms.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>Alzheimer’s
• SuperAgers with superior memories have more protective short RNAs in their brains

Alzheimer’s disease, which is expected to have affected about 6.7 million patients in the U.S. in 2023, results in a substantial loss of brain cells. But the events that cause neuron death are poorly understood.

A new Northwestern Medicine study shows that RNARibonucleic acid (RNA) is a polymeric molecule similar to DNA that is essential in various biological roles in coding, decoding, regulation and expression of genes. Both are nucleic acids, but unlike DNA, RNA is single-stranded. An RNA strand has a backbone made of alternating sugar (ribose) and phosphate groups. Attached to each sugar is one of four bases—adenine (A), uracil (U), cytosine (C), or guanine (G). Different types of RNA exist in the cell: messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA).” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>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 DNADNA, or deoxyribonucleic acid, is a molecule composed of two long strands of nucleotides that coil around each other to form a double helix. It is the hereditary material in humans and almost all other organisms that carries genetic instructions for development, functioning, growth, and reproduction. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>DNA damage in Alzheimer’s and aged brains. Short strands of protective RNAs are decreased during aging, the scientists report, which may allow Alzheimer’s to develop.

The study also found that older individuals with a superior memory capacity (known as SuperAgers) have higher amounts of protective short RNA strands in their brain cells. SuperAgers are individuals aged 80 and older with a memory capacity of individuals 20 to 30 years younger.

“Nobody has ever connected the activities of RNAs to Alzheimer’s,” said corresponding study author Marcus Peter, the Tom D. Spies Professor of Cancer Metabolism at Northwestern UniversityEstablished in 1851, Northwestern University (NU) is a private research university based in Evanston, Illinois, United States. Northwestern is known for its McCormick School of Engineering and Applied Science, Kellogg School of Management, Feinberg School of Medicine, Pritzker School of Law, Bienen School of Music, and Medill School of Journalism. ” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>Northwestern University Feinberg School of Medicine. “We found that in aging brain cells, the balance between toxic and protective sRNAs shifts toward toxic ones.”

The paper was published on January 18 in Nature Communications<em>Nature Communications</em> is a peer-reviewed, open-access, multidisciplinary, scientific journal published by Nature Portfolio. It covers the natural sciences, including physics, biology, chemistry, medicine, and earth sciences. It began publishing in 2010 and has editorial offices in London, Berlin, New York City, and Shanghai. ” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>Nature Communications.

Relevance beyond Alzheimer’s disease

The Northwestern discovery may have relevance beyond Alzheimer’s. “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 said.

New avenue for treatment

The findings also point to a new way for treating Alzheimer’s and potentially other neurodegenerative diseases.

Alzheimer’s is characterized by a progressive occurrence of amyloid-beta plaques, tau neurofibrillary tangles, scarring and ultimate brain cell death.

“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% of the effort — and preventing tau phosphorylation or tangles,” Peter said. “However, treatments aimed at reducing amyloid plaques have not yet resulted in an effective treatment that is well tolerated.

“Our data support the idea that 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.”

Such drugs exist, Peter said, but they would need to be tested in animal models and improved.

The next step in Peter’s research is to determine in different animal and cellular models (as well as in brains from Alzheimer’s patients) the exact contribution of toxic sRNAs to the cell death seen in the disease and screen for better compounds that would selectively increase the level of protective sRNAs or block the action of the toxic ones.

What are toxic and protective short RNAs?

All our gene information is stored in form of DNA in the nucleus of every cell. To turn this gene information into the building blocks of life, DNA needs to be converted into RNA which is used by cell machinery to produce proteins. RNA is essential for most biological functions.

In addition to these long coding RNAs, 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.

Peter and colleagues 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 resulting in cell death. Their data suggest 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 speciesA species is a group of living organisms that share a set of common characteristics and are able to breed and produce fertile offspring. The concept of a species is important in biology as it is used to classify and organize the diversity of life. There are different ways to define a species, but the most widely accepted one is the biological species concept, which defines a species as a group of organisms that can interbreed and produce viable offspring in nature. This definition is widely used in evolutionary biology and ecology to identify and classify living organisms.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>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.

Key findings

• The amount of protective sRNAs is reduced in the aging brain.
• Adding back protective miRNAs 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.)

How the study worked:

Scientists analyzed the brains of Alzheimer’s disease mouse models, the brains of young and old mice, induced pluripotent stem cell-derived neurons from normal individuals (both young and aged) and from Alzheimer’s patients, the brains of a group of older individuals over 80 with memory capacity equivalent to individuals 50 to 60 years old, and multiple human brain-derived neuron-like cell lines treated with amyloid beta fragments, a trigger of Alzheimer’s.

Reference: “Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer’s disease and aging” by Bidur Paudel, Si-Yeon Jeong, Carolina Pena Martinez, Alexis Rickman, Ashley Haluck-Kangas, Elizabeth T. Bartom, Kristina Fredriksen, Amira Affaneh, John A. Kessler, Joseph R. Mazzulli, Andrea E. Murmann, Emily Rogalski, Changiz Geula, Adriana Ferreira, Bradlee L. Heckmann, Douglas R. Green, Katherine R. Sadleir, Robert Vassar and Marcus E. Peter, 18 January 2024, Nature Communications.
DOI: 10.1038/s41467-023-44465-8

Northwestern co-authors on the study include first author Bidur Paudel, Si-Yeon Jeong, Ashley Haluck-Kangas, Elizabeth T. Bartom, Kristina Fredriksen, Amira Affaneh, John A. Kessler, Joseph R. Mazzulli, Andrea E. Murmann, Emily Rogalski (formerly of Northwestern), Changiz Geula, Adriana Ferreira, Katherine R. Sadleir and Robert Vassar.

This work was supported by National Institutes of HealthThe National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. Founded in 1887, it is a part of the U.S. Department of Health and Human Services. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program. With 27 different institutes and centers under its umbrella, the NIH covers a broad spectrum of health-related research, including specific diseases, population health, clinical research, and fundamental biological processes. Its mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>National Institutes of Health grants R35CA197450, R35CA231620, R01NS090993, R01AG030142, R01AG045571, R56AG045571, R01AG067781, U19AG073153, P30AG072977, P30AG13854 and R01NS124783 and L40CA231423.