Stop neurodegeneration
Restoring energy exchange in the brain preserved the cognitive abilities of mice with Alzheimer's disease
Daria Spasskaya, N+1
Scientists in experiments on mice found that Alzheimer's disease is accompanied by depletion of the intracellular metabolite NAD+, which is involved in a variety of redox reactions. Its replenishment slows down the progress of the disease, the researchers write in an article published in the Proceedings of the National Academy of Sciences (Hou et al., NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency).
Despite the fact that a significant contribution to neurodegeneration in Alzheimer's disease is made by the formation of plaques from beta-amyloid protein in nervous tissue, many non-specific processes are also involved in the pathogenesis of the disease, such as oxidative stress, impaired DNA repair and inflammation. For model animals with mutations in the genes of DNA repair enzymes, premature aging and neurodegeneration are characteristic. In addition, in many neurodegenerative diseases, mitochondria malfunction is observed, which is accompanied by a decrease in the level of ATP synthesis and a deterioration in the energy supply of nervous tissue.
The key cofactor in the work of mitochondria and DNA repair is the cellular metabolite NAD (nicotinamide adenine dinucleotide). It has been shown that neurons, due to the high level of energy exchange, are particularly sensitive to the lack of the oxidized form of NAD (NAD+). The addition of precursors of this metabolite to animal food delayed the development of a pathological phenotype characteristic of aging, and even prolonged life, as was shown in nematodes and mice.
Turning OVER in a Cage (Wikimedia Commons)
Researchers from the National Institute of Aging in Baltimore (USA), in collaboration with the Danish Scientific Center for Aging, have created a new mouse model with a mutation in the Polß gene encoding DNA polymerase β. This enzyme is necessary for the repair of oxidative DNA damage, which is most often found in neurodegenerative diseases. Also, a mutant form of beta-amyloid (Aß), prone to aggregation and plaque formation (3xTgAD mice), was expressed in the brain in model mice.
In patients with Alzheimer's disease, the appearance of visible disorders is usually associated with a decrease in the number of neurons. At the same time, popular mouse models develop cognitive impairments due to the formation of amyloid plaques, but there is no significant death of neurons. In Polß mutant mice (AD/Polß+/−), the level of DNA damage and oxidative stress in the nervous tissue was significantly higher than in the original model mice (AD), and this led to significant neuron death. Thus, the new model better reflected the processes occurring in the human brain in Alzheimer's disease.
The researchers suggested that mice with neurodegeneration in the brain have a deficiency of the oxidized form of NAD, and that restoring its level will improve the condition of the animals. To test this hypothesis, several groups of adult wild-type mice with model mutations were added to the water of the precursor of NAD nicotinamide riboside (HP) for six months. The control groups were not given it. During the last three months, the mice underwent behavioral and metabolic tests.
By the end of the experiment, it turned out that in control mice AD/Polß+/−the level of NAD+ in the brain was significantly reduced compared to both wild-type mice and "normal" AD mice. In addition, they performed the worst on tests and demonstrated learning disabilities. The addition of HP to the diet restored the learning ability and memory of animals to the level of the wild type.
A. Scheme of the experiment. Four groups of mice participating in it are indicated in different colors. B. The ratio of the oxidized form of NAD to the reduced one in the brain of mice from different groups who received (orange bars) a food additive (NR), or did not receive (black bars). C. Results of the behavioral test in the Morris Water maze. Mice with a repair disorder have the worst memory and cannot remember the position of the platform in the maze (blue line). D. The use of the precursor NAD (NR) by animals improves the learning ability of model mice in the same test (from an article in PNAS).
At the physiological level, the precursor of NAD in the form of a dietary supplement restored synaptic plasticity in the hippocampus in sick mice, reduced the level of inflammation in the nervous tissue and enhanced neurogenesis. In the brains of mice, the amount of oxidative DNA damage decreased and the percentage of cells going into apoptosis ("committing suicide") decreased. At the same time, the level of NAD did not affect the aggregation of beta-amyloid in any way.
The researchers also conducted an experiment on human connective tissue cells taken from a patient with Alzheimer's disease. It turned out that the addition of the NAD precursor to the medium during the day reduced the amount of reactive oxygen species produced by mitochondria and reduced the amount of oxidized DNA.
Previously, the effect of NAD precursors was shown by other researchers on model animals with ataxia, Parkinson's disease, hearing loss and other models of Alzheimer's disease. These results mean that in neuropathologies, the deterioration of the condition is largely determined by nonspecific intracellular processes. Therefore, a decrease, for example, in the amount of reactive oxygen species in neurons, can slow down the pathogenesis of the disease to a significant extent. The authors hope that this approach will soon reach trials in patients with Alzheimer's disease, for which there is currently no effective therapy.
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