New cause of neuron death in Alzheimer’s discovered

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

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Alzheimer’s disease affects a significant number of people, with around 6.7 million patients expected in the U.S. in 2023. It leads to a substantial loss of brain cells, but the specific events causing this cell death are poorly understood.

A recent study from Northwestern Medicine suggests that RNA interference, a process where RNA molecules regulate the expression of genes, may play a crucial role in Alzheimer’s. For the first time, scientists have identified short strands of toxic RNAs that contribute to the death of brain cells and DNA damage in both Alzheimer’s and aged brains. The researchers found that these protective short RNA strands decrease with age, possibly contributing to the development of Alzheimer’s.

Interestingly, the study also discovered that older individuals with exceptional memory capacity, referred to as “SuperAgers” (aged 80 and older with memory comparable to individuals 20 to 30 years younger), have higher amounts of these protective short RNA strands in their brain cells. This finding could offer insights into the mechanisms behind cognitive resilience in some individuals as they age.

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

Peter said, “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.”

The findings from Northwestern University’s study on RNA interference and Alzheimer’s disease may extend beyond Alzheimer’s itself. The data suggest a new explanation for the common observation in various neurodegenerative diseases where individuals experience decades of symptom-free life. Then, the disease gradually sets in as cells lose their protective mechanisms with age.

Peter said, “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. 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.”

Drugs with the potential to address the issues related to toxic short RNAs (sRNAs) exist. However, before these drugs can be considered for use, they need to undergo testing in animal models and undergo further improvements.

The next phase of Peter’s research involves investigating the precise role of toxic sRNAs in causing cell death in Alzheimer’s. This will be done by studying different animal and cellular models and examining the brains of individuals with Alzheimer’s disease. The aim is to understand the specific contribution of toxic sRNAs to the cell death observed in the disease. Additionally, the research will involve screening for better compounds that can selectively increase the levels of protective sRNAs or block the actions of the harmful ones.

Our genetic information is stored in the form of DNA within the nucleus of every cell. To translate this gene information into the fundamental components of life, DNA needs to be converted into RNA, which is then used by the cell machinery to create proteins. RNA plays a crucial role in various biological functions.

In addition to long coding RNAs, short RNAs (sRNAs) don’t code for proteins but have essential functions in the cell. One class of these sRNAs suppresses long-coding RNAs through RNA interference, effectively silencing the proteins that the long RNAs encode.

Peter and his colleagues have discovered very short sequences within some of these sRNAs that, when present, can cause cell death by blocking the production of proteins necessary for cell survival. Their findings suggest that these toxic sRNAs contribute to the end of neurons, playing a role in the development of Alzheimer’s disease.

Protective sRNAs usually inhibit these toxic sRNAs, with one type known as microRNAs acting as the main species of protective sRNAs. MicroRNAs play multiple regulatory roles in cells and act like guards, preventing toxic sRNAs from entering the cellular machinery that carries out RNA interference. However, as individuals age, these guards decrease, allowing toxic sRNAs to harm cells.

The scientists conducted a comprehensive analysis by examining various sources, including:

  • Brains of Alzheimer’s Disease Mouse Models.
  • Brains of Young and Old Mice.
  • Induced Pluripotent Stem Cell-Derived Neurons.
  • Brains of Older Individuals (Over 80) with Exceptional Memory Capacity.
  • Human Brain-Derived Neuron-Like Cell Lines. Using cell lines that resemble neurons and treating them with amyloid beta fragments are known triggers of Alzheimer’s disease.

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.)

Journal Reference:

  1. 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, Marcus E. Peter. Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer’s disease and aging. Nature Communications, 2024; 15 (1) DOI: 10.1038/s41467-023-44465-8