Dementia, particularly Alzheimer’s Disease, is one of the leading causes of death in the world. According to the World Health Organization (WHO), Alzheimer’s Disease is ranked #7, killing 1.8 million lives (2021). Sadly, no cure has been made to significantly reduce the cases of Alzheimer’s Disease. The University of Oslo, however, has recently found a mechanism that can halt the rate of Alzheimer’s neurological deficits.
What is Alzheimer’s Disease?
Alzheimer’s Disease is progressive and occurs when there is a substantial buildup of amyloid plagues and neurofibrillary tangles in the brain. These things can cause nerve cells to die, resulting in the brain shrinking. Symptoms of Alzheimer’s Disease can include…
1. Memory Loss- Forgetting conversations, events, and places that were considered important. At a more severe stage, individuals can forget the names of their family members and close friends.
2. Difficulty in Making Reasonable Decisions/Judgements- Reasonable decisions could just be as simple as forgetting to wear gloves when taking a hot tray out of an oven or wearing a raincoat for the entire day when the weather forecast mentioned that no rain would appear. People that have Alzheimer’s may struggle in these everyday situations.
3. Significant Mood & Behavior Changes- Loss of interest in activities that were considered valuable for them or feeling as if they were “wandering” around the environment they live in are some changes that can occur when Alzheimer’s Disease is present. Additionally, mood swings are more prevalent along with a sudden increase in anger or aggression.
Although there is no current cure, two treatments, donanemab (Kisunla) and lecanemab (Leqembi) both remove beta-amyloid, a core component of amyloid plaque buildup, which reduces functional decline for people that are in the early stages of Alzheimer’s. With the new mechanism, scientists are now on track to finding a cure.
Why this Study is Important
Alternative splicing events or ASEs in RNA serve as indicators for aging and Alzheimer’s disease. Nicotinamide adenine dinucleotide (NAD+) is responsible for keeping the brain healthy and protected. NAD+ precursors such as nicotinamide riboside and nicotinamide mononucleotide inhibited a protein called pTau, a highly accurate biomarker for Alzheimer’s disease. Prior to this investigation, not much research regarding NAD+ along with ASEs in tauopathies was conducted.
Through this study, scientists from the University of Oslo used mammalian cells, nematodes, and postmortem human brain tissue. Additionally, they used transcriptomic data mining, 3D protein models, and wet laboratory technologies. What they discovered could prove important for future research in the fight against Alzheimer’s Disease.
The Proposed Mechanism & Results
Pathways in axon genesis, axon extension, axon guidance, oxygen metabolism, mitochondrion localization, and autophagy were all treated with NAD+ in tauopathy models. It was then shown that there was a protein named EVA1C and is essential for RNA-splicing events. When NAD+ supplementation was present in these pathways, there was a significant improvement in memory performance and brain function. However, without the presence of EVA1C, these NAD+ benefits were lost and hence, the protein is important in mediating the nervous system. The study further supports this by correlating Alzheimer’s Disease with low levels of EVA1C.
DeepPPI, an AI model used for solving complex protein features, found that NAD+ induced pathways formed a specific isoform of EVA1C that binded to essential proteins that are crucial for protein folding and clearance. Specifically, these proteins are HSP70 and BAG1/BAG3. Heat shock proteins are molecular chaperones that help fold proteins, protect cells from stress factors such as disease, heat and injury, and regulates cell death (apoptosis). This is co-chaperoned with BAG1/BAG3 which also regulate cell death and stress responses. Unfortunately, interactions on the many isoforms of EVA1C with HSP70 and BAG1/BAG3 remain.
How the Future Looks
Establishing the groundwork between NAD+ and EVA1C is essential for the development of new treatments that involve NAD+ supplementation. As seen in the study, NAD+ levels are crucial for maintaining brain function and delaying cognitive decline. With that, humanity is one step closer towards a cure for Alzheimer’s Disease.