A Mouse Model of Sporadic Alzheimer's Disease with Elements of Major Depression.

After olfactory bulbectomy, animals are often used as a model of major depression or sporadic Alzheimer's disease and, hence, the status of this model is still disputable. To elucidate the nature of alterations in the expression of the genome after the operation, we analyzed transcriptomes of the cortex, hippocampus, and cerebellum of the olfactory bulbectomized (OBX) mice. Analysis of the functional significance of genes in the brain of OBX mice indicates that the balance of the GABA/glutamatergic systems is disturbed with hyperactivation of the latter in the hippocampus, leading to the development of excitotoxicity and induction of apoptosis in the background of severe mitochondrial dysfunction and astrogliosis. On top of this, the synthesis of neurotrophic factors decreases leading to the disruption of the cytoskeleton of neurons, an increase in the level of intracellular calcium, and the activation of tau protein hyperphosphorylation. Moreover, the acetylcholinergic system is deficient in the background of the hyperactivation of acetylcholinesterase. Importantly, the activity of the dopaminergic, endorphin, and opiate systems in OBX mice decreases, leading to hormonal dysfunction. On the other hand, genes responsible for the regulation of circadian rhythms, cell migration, and innate immunity are activated in OBX animals. All this takes place in the background of a drastic downregulation of ribosomal protein genes in the brain. The obtained results indicate that OBX mice represent a model of Alzheimer's disease with elements of major depression.

[The study of lipofuscin levels in the 5xFAD mouse model of Alzheimer's disease.]

In this study, we evaluated the change in the level of lipofuscin, an autofluorescent aging pigment, in brain and peripheral tissues in a transgenic mouse model of Alzheimer's disease (AD) - 5xFAD. A comparative analysis of the content of lipofuscin in homogenates of the liver, kidneys, heart, and various parts of the brain of 5xFAD mice, as well as control mice from the same litters of different ages, was carried out. The data obtained correlate well with the concept of lipofuscin as an aging pigment - its amount increases with age in both control and 5xFAD mice. We noted accumulation of lipofuscin progressive with age in 5xFAD mice, which is detected both in different parts of the brain and in peripheral organs. At the same time, the level of lipofuscin was increased even in newborn day-old mice 5xFAD. Thus, an increase in the level of lipofuscin in 5xFAD mice is one of the earliest disorders that manifests itself not only in the brain, but also in other organs.

[Lipofuscin and mitolipofuscin in organs of young and adult rats.]

A comparison of the lipofuscin (aging pigment) content in four organs (liver, kidney, heart, brain) of young and adult rats, as well as in a suspension of hepatic mitochondria, was made. It was demonstrated that mitochondrial lipofuscin - mitolipofuscin, fluorescing in the blue region, makes the main contribution to hepatic lipofuscin. It is assumed that mitolipofuscin in other organs also makes a significant contribution. It is shown that accumulation of lipofuscin with age occurs in all organs of rats, but least of all in the brain. In addition to fluorescent lipofuscin, non-fluorescent protein aggregates are found in all organs, the largest number of which is found in the heart. Among them, a significant proportion is covalently cross-linked aggregates that are not destroyed by detergents. Their number also increases with age.