Nmnat1 Modulates Mitochondrial Oxidative Stress by Inhibiting Caspase-3 Signaling in Alzheimer’s Disease

• Published in: Journal of molecular neuroscience 2021-07, Vol.71 (7), p.1467-1472
• Main Authors: Jiang, Huayu, Wan, Zhiwen, Ding, Ying, Yao, Zhiwen
• Format: Article
• Language: English
• Subjects: Adenine; Akinesia; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Apoptosis; bcl-2-Associated X Protein - biosynthesis; bcl-2-Associated X Protein - genetics; Biomedical and Life Sciences; Biomedicine; Caspase 3 - physiology; Caspase-3; Cell Biology; Cognitive ability; Corpus Striatum - metabolism; Dopamine receptors; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Enzyme Activation; Hydroxylase; Maze Learning; Mice; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; NAD; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Neurochemistry; Neurodegenerative diseases; Neurology; Neurons; Neurosciences; Nicotinamide; Nicotinamide adenine dinucleotide; Nicotinamide-Nucleotide Adenylyltransferase - physiology; Open Field Test; Oxidative Stress; Proteomics; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - genetics; Random Allocation; Recombinant Proteins - metabolism; Risk analysis; Risk factors; Substantia nigra; Substantia Nigra - metabolism; Superoxide dismutase; Superoxide Dismutase-1 - biosynthesis; Superoxide Dismutase-1 - genetics; Toxicity; Transgenic mice; Tyrosine; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - biosynthesis; Tyrosine 3-Monooxygenase - genetics; Up-Regulation
• ISSN: 0895-8696; 1559-1166
• DOI: 10.1007/s12031-020-01781-8

Nigrostriatal pathway disturbance is one of the major pathogenic factors in Alzheimer’s disease (AD). Dopaminergic neuron dysfunction results in bradykinesia and akinesia (inability to initiate movement), indicating a significant risk factor for substantia nigra pars compacta lesions. Furthermore, the nicotinamide adenine dinucleotide (NAD + ) is associated with Aβ toxicity decline in AD therapy. Nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) is an essential enzyme that preserves normal neuronal function and protects neurons from insult. This study aimed to investigate the potential therapeutic effects of Nmnat1 and its underlying mechanisms in a triple-transgenic mouse model of AD (3xTgAD). Results showed that Nmnat1 improved the substantial behavioral measures of cognitive impairments compared with the 3xTgAD control. Additionally, Nmnat1 overexpression significantly increased tyrosine hydroxylase-positive neurons and anti-apoptotic protein Bcl2 and caspase-3 expression levels in 3xTgAD mice. Nmnat1 also effectively controlled SOD1 activation. In conclusion, Nmnat1 substantially decreases multiple AD-associated pathological characteristics at least partially by the increase of caspase-3 activation.