A groundbreaking study conducted by Northwestern Medicine has shed light on the role of RNA interference in Alzheimer's disease, uncovering the significance of imbalances between toxic and protective RNA strands in brain cell loss. The findings offer new avenues for potential treatments focused on RNA interference.

Alzheimer's disease affects millions of individuals in the United States, with an estimated 6.7 million patients projected for 2023. However, the events that trigger neuron death in this neurodegenerative disease have remained poorly understood.

For the first time, scientists have identified short toxic RNA strands that contribute to the death of brain cells and DNA damage in both Alzheimer's and aged brains. Additionally, the study revealed that the amount of protective short RNA strands decreases with aging, potentially allowing Alzheimer's to develop.

Intriguingly, the research also found that "SuperAgers," individuals aged 80 and older with memory capacities comparable to those 20 to 30 years younger, possess higher levels of protective short RNA strands in their brain cells. This observation suggests that these protective RNA strands may play a crucial role in maintaining cognitive function.

Lead author Marcus Peter, the Tom D. Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine, highlighted the groundbreaking nature of the study, stating, "Nobody has ever connected the activities of RNAs to Alzheimer's. We found that in aging brain cells, the balance between toxic and protective sRNAs shifts toward toxic ones."

Recognizing the potential broader implications beyond Alzheimer's, Peter explained that the study provides a new explanation for the decades-long period of symptom-free life in various neurodegenerative diseases before symptoms gradually manifest as cells lose their protection with age.

Moreover, the findings present a promising new approach to Alzheimer's treatment and potentially other neurodegenerative diseases. Traditionally, drug development efforts have focused on targeting amyloid plaques and tau phosphorylation, to limited success. However, the data support the notion that stabilizing or increasing the amount of protective short RNAs in the brain could be a novel approach to halt or delay Alzheimer's and neurodegeneration.

While drugs that can enhance the activity of these protective RNA strands already exist, further research utilizing animal models and Alzheimer's patient brains is necessary to pinpoint the exact contribution of toxic RNA strands to cell death and identify better compounds that selectively boost the levels of protective RNA strands or hinder the effects of toxic ones.

The study's findings are rooted in the understanding of different types of RNA in cells. RNA, like DNA, plays a crucial role in cellular functions, including the production of proteins. In addition to long coding RNAs, which are involved in protein production, there are short RNAs (sRNAs) that do not code for proteins but perform critical functions within the cell. One class of sRNAs, called microRNAs, act as protective strands by suppressing long coding RNAs through a process known as RNA interference.

The study showed that very short sequences in certain sRNAs can lead to cell death by blocking the production of essential survival proteins. These toxic sRNAs are normally inhibited by protective sRNAs, such as microRNAs. However, with aging, the levels of protective sRNAs decrease, allowing the toxic sRNAs to damage cells.

The research involved analyzing the brains of Alzheimer's disease mouse models, young and old mice, neurons derived from normal individuals of different ages, neurons from Alzheimer's patients, the brains of a group of older individuals with exceptional memory capacity, and various human brain-derived cell lines treated with triggers of Alzheimer's.

The groundbreaking study opens a promising new chapter in Alzheimer's research, highlighting the crucial role of RNA interference and imbalances in toxic and protective RNA strands. As scientists delve deeper into these discoveries, the hope for effective treatments and interventions to halt or delay the devastating progression of Alzheimer's disease grows stronger.

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.