Alzheimer’s disease (AD), which is the most common cause of dementia, impacts nearly 40 million people around the world, leading to a gradual decline in memory and independence. Despite significant research efforts over the years, effective treatments that can stop or reverse this devastating condition remain elusive.
A key factor in neuronal dysfunction associated with AD is the protein tau. This protein typically helps maintain neuronal stability—similar to how train tracks guide trains. However, in certain conditions, tau can undergo abnormal changes and start to clump together, disrupting this system. This, in turn, causes neuronal damage and memory loss.
Recently, an international team of researchers disclosed a new mechanism where enhancing the natural metabolite NAD⁺ may offer protection against brain degeneration related to AD. Their findings, detailed in a paper titled “NAD⁺ reverses Alzheimer’s neurological deficits via regulating differential alternative RNA splicing of EVA1C,” were published in Science Advances.
The study was spearheaded by Associate Professor Evandro Fei Fang from the University of Oslo and Akershus University Hospital in Norway, alongside Professor Oscar Junhong Luo from Jinan University in China and Associate Professor Joana M. Silva from the University of Minho in Portugal.
Understanding NAD⁺ and Brain Health
NAD⁺ (nicotinamide adenine dinucleotide, in its oxidized form) is an essential metabolite linked to energy metabolism and the resilience of neurons. Unfortunately, its levels tend to decrease with age and in various neurodegenerative disorders.
“Early studies indicated that adding NAD⁺ precursors, like nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), could provide therapeutic gains in animal models of AD and in early human trials,” says first author Alice Ruixue Ai. “Yet, the specific molecular mechanisms driving these benefits are mostly unclear.”
The research unveiled that NAD⁺ operates through a newly recognized RNA-splicing pathway. This pathway is regulated by a protein named EVA1C, pivotal for the RNA splicing process. RNA splicing allows a single gene to yield various protein isoforms, some of which may exhibit unique effects. Dysregulated splicing has recently been identified as a risk factor for AD.
When NAD⁺ levels are elevated, EVA1C can help rectify errors in RNA splicing, thereby enhancing the function of numerous genes critical for brain health. This improvement may reverse neurodegenerative damage typically induced by tau.
Validation Across Species
To validate their findings, the research team employed a thorough approach, including computational predictions and tests across different animal models like worms and mice, as well as human brain samples.
They observed age-related alterations in RNA splicing in specific worms. By supplementing with NAD⁺, they could fix the splicing issues triggered by the toxic tau. In mice with tau-related mutations, NAD⁺ supplementation improved RNA splicing, restored brain function, and enhanced memory performance.
“Importantly, when we disrupted the EVA1C gene, those benefits were diminished, emphasizing EVA1C’s crucial role in NAD⁺-induced neuroprotection,” highlights Associate Professor Evandro Fei Fang-Stavem.
Supporting these animal studies, EVA1C levels were also notably reduced in brain cells from individuals with early stage AD.
AI in Mechanism Discovery
To delve deeper into EVA1C’s function, the team utilized an AI-driven platform to predict protein interactions, analyzing data related to structure, sequence, and evolution from millions of proteins.
This investigation revealed that NAD⁺ promotes a specific form of EVA1C that efficiently binds to crucial proteins involved in protein folding and clearance—it connects metabolic balance, RNA splicing, and protein management, all three processes significantly compromised in AD.
Prospects for New Alzheimer’s Treatments
By linking NAD⁺ with EVA1C, this study paves the way for new therapeutic strategies and the refinement of NAD⁺ augmentation methods in humans.
“We suggest that maintaining NAD⁺ levels could help sustain neuronal identity and slow cognitive decline, setting the stage for combination therapies targeting RNA splicing,” Ai concludes.
