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"Boosting levels of a certain molecule that declines with age was found to restore memory and brain function in Alzheimer’s disease (AD) models – not just by improving energy metabolism, as previously thought, but by fixing RNA splicing errors that disrupt hundreds of genes crucial to neuron health. ...
a team of scientists ... has uncovered a mechanism driven by the natural metabolite, oxidized nicotinamide adenine dinucleotide (NAD⁺), which can shield the brain from the progressive damage of AD. ...
"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." ..."
"... 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. ..."
From the abstract:
"Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer’s disease (AD).
As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD+) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD+ enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive.
This study shows that NAD+ augmentation corrects the ASEs of many genes via a key protein, EVA1C (epithelial V-like antigen 1 homolog C), which is involved in neuronal development and activities.
EVA1C is reduced in the hippocampus in patients with AD compared to cognitively normal ones.
NAD+-induced memory retention is partially dependent on EVA1C, as adeno-associated virus–based Eva1c knockdown in the hippocampal CA1 region annuls NAD+-induced memory improvement in pathological Tau–bearing mice.
We propose that NAD+ reduces AD pathologies, at least partially, via amplification of the NAD+-EVA1C splicing axis, pointing to a potential splice-switching therapy for AD."
NAD⁺ restores memory in Alzheimer’s’ disease models by correcting RNA errors "A groundbreaking international study shows how boosting a natural molecule can help restore memory in animal models of Alzheimer’s disease. The new study offers hope for developing new therapies for patients with Alzheimer’s disease."
NAD+ reverses Alzheimer’s neurological deficits via regulating differential alternative RNA splicing of EVA1C (open access)
Fig. 1. Compromised mRNA splicing in Tau pathology and aging.
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