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NAD+ - and EVA1-C-dependent reversal of neurological deficits is mediated by differential alternative RNA splicing in tauopathic animal models

ABSTRACT: Aberrant alternative splicing events (ASEs) are emerging as a new hallmark of aging and are linked to age-related neurodegenerative pathologies such as Alzheimer’s disease (AD). AD brains are characterized by abundant intracellular proteinaceous aggregates, including neurofibrillary tangles (NFTs). Although NAD+ and related metabolites can slow down AD progression, the effects of NAD+ on ASEs in AD remain unclear. This study investigates the relationships between NAD+ metabolism, ASEs and AD or AD-like pathologies including tauopathies using deep-learning AI-based algorithms to predict protein structures and protein-protein interactions as well as experimental tauopathy models including hTau.P301S transgenic mice and transgenic hTau[P301L] Caenorhabditis elegans. Mouse transcriptomic data were mined to detect ASEs that were differentially induced in the presence of NAD+ precursor nicotinamide riboside (NR) with specific focus on the Eva1-C locus. The results reveal that the relative abundance of Eva1-C isoforms is sensitive to both the concentration of NR and to tauopathy genotype. NAD+ abundance/metabolic status modulates ASEs and the expression of EVA1-C isoforms, which in turn regulate the interaction with the key proteins, BAG-1 and HSP70, involved in orchestrating protein homeostasis. Importantly, EVA1-C is dramatically reduced in the postmortem entorhinal cortex and hippocampal neurons from 20 Braak 5/6 AD patients compared to 20 of cognitive normal humans. Thus, this study supports the novel idea that NAD+ metabolism modulates abundance of specific mRNA isoforms, and that ASEs influence disease progression in model tauopathies and potentially AD. These results could facilitate future development of NAD+-based splice-switching therapeutics for AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE279334 | GEO | 2025/10/03

REPOSITORIES: GEO

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Project description:Alzheimer's disease (AD) is a severe neurodegenerative disorder. Clinical trials to identify agents to treat AD have failed, and its underlying molecular pathology and etiology remain elusive. Neuroinflammation is thought to play a key role in the progression of AD. Emerging evidence has identified lower Nicotinamide adenine dinucleotide (NAD+) levels as a major factor in neurodegeneration, especially in AD. NAD+ is an important metabolite in all human cells, as it is at the convergence of many central processes in cellular and mitochondrial maintenance, including DNA repair and mitophagy (the degradation of damaged mitochondria). Our previous work found that treatment of 3xTgAD mice with an NAD+ precursor, nicotinamide riboside (NR), can improve key AD features including tau phosphorylation and learning deficits in mice. Here we used the APP/PS1 AD mouse model to interrogate the effect of NR on neuroinflammation. Microarray analysis revealed major changes in pathways and genes associated with inflammation and the APP/PS1 mice had lower NAD+ levels than WT mice. Thus, seven months old mice were treated with NR for five months and their NAD+/NADH ratio increased. Brain neuroinflammation decreased as determined by decreased activation of astrocytes and microglia, decreased pro-inflammatory cytokines and chemokines in the brains of the APP/PS1 mice. NR decreased neuroinflammation by lowering the NLRP3 inflammasome and NF-κB pathways. NR also attenuated DNA damage and apoptosis in the AD mouse brains. NR dramatically decreased senescence in the hippocampus and cortex of AD mice, relative to controls. Recent studies suggest that cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) activation are associated with DNA damage and senescence. cGAS-STING was activated in AD mice and decreases after NR treatment. Suggesting that NR can diminish neuroinflammation and senescence through the cGAS-STING pathway. NR treatment also greatly improved cognition and synaptic function in the APP/PS1 mice. We propose that the cGAS-STING pathway should be evaluated as a potential novel therapeutic target in AD.

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NAD+ - and EVA1-C-dependent reversal of neurological deficits is mediated by differential alternative RNA splicing in tauopathic animal models

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