Targeting RNA splicing errors protects against tau-induced neurodegeneration

Alzheimer's Disease (AD), the leading cause of dementia, affects nearly 40 million individuals globally, resulting in a gradual loss of memory and independence. Despite extensive research over the past decades, no treatments have been found that can halt or reverse the progression of this devastating disease.

In AD, a major contributor to neuronal dysfunction is the protein tau. Tau typically plays a crucial role in keeping the internal structure of neurons stable, much like train tracks help trains stay on course. However, in some diseases, tau undergoes abnormal modifications and starts to aggregate, disrupting this transport system, thus leading to neuronal damage and subsequent memory loss.

An international team of researchers has reported a new mechanism by which boosting the natural metabolite NAD⁺ can protect the brain from the degeneration associated with AD. Their paper, titled "NAD⁺ reverses Alzheimer's neurological deficits via regulating differential alternative RNA splicing of EVA1C", is published in the renowned journal Science Advances.

The team is led by Associate Professor Evandro Fei Fang from the University of Oslo and Akershus University Hospital, Norway, in collaboration with Professor Oscar Junhong Luo from Jinan University, China, and Associate Professor Joana M. Silva from the University of Minho, Portugal.

How NAD⁺ supports brain health

NAD⁺ (Nicotinamide adenine dinucleotide, oxidised form) is a vital metabolite involved in energy metabolism and neuronal resilience in the body. It is normally declined with age and especially in various neurodegenerative diseases.

Preliminary studies have shown that supplementation with NAD⁺ precursors, such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), can offer therapeutic benefits in AD animal models and early clinical trials. However, the molecular mechanisms behind these benefits remain largely unclear."

Alice Ruixue Ai, University of Oslo

The new study reveals that NAD⁺ works through a previously unidentified RNA-splicing pathway. This pathway is regulated by a protein called EVA1C, which plays an essential role in the process of RNA splicing. RNA splicing allows a single gene to produce multiple isoforms of a protein, and one isoform may show distinctive effects to the other isoforms. Its dysregulation is one of the most recently acknowledged risk factor for AD.

The researchers discovered that when NAD⁺ levels are increased, EVA1C helps correct mistakes in RNA splicing. This restoration process improves the function of hundreds of genes, many crucial for brain health, which can help reverse the neurodegenerative damage caused by tau.

Cross-species validation from worms to mice to the human brain

To demonstrate the impact of this mechanism, the researchers used a comprehensive approach that included computer predictions and validation in different animal models, including worms, mice, as well as human brain samples.

They first identified age-related changes in RNA splicing in a specific type of worm. They found that adding NAD⁺ could correct the splicing issues caused by the toxic tau protein. In mice with tau-related mutations, NAD⁺ supplements improved RNA splicing, restored brain function, and enhanced memory performance. "Notably, we found when the EVA1C gene was knocked down, these benefits were lost, confirming that EVA1C is essential for NAD⁺-mediated neuroprotection", Associate Professor Evandro Fei Fang-Stavem says.

Aligned with these animal studies, EVA1C levels was significantly reduced in brain cells from people with early AD.

Using AI to uncover the mechanism

To further investigate how EVA1C works, the team used an AI-driven platform to predict how proteins interact with one another, analysing structural, sequential, and evolutionary data from millions of proteins. This analysis revealed that NAD⁺ promotes a specific form of EVA1C that efficiently binds to essential proteins, which are central to protein folding and clearance. This connection links metabolic homeostasis, RNA splicing processes and protein management, three processes that are critically impaired in AD.

Towards new Alzheimer's treatments

By establishing the connection between NAD⁺ and EVA1C, this study lays the groundwork for the development of new therapies and optimization of NAD⁺ augmentation strategies in humans. "We propose that maintaining NAD⁺ levels could help preserve neuronal identity and delay cognitive decline, paving the way for combination treatments to enhance RNA splicing", Ai says.