A mouse model of sporadic Alzheimer’s disease with elements of major depression

Abstract

Animals after bulbectomy are often used as a model of major depression or sporadicAlzheimer’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 (RNA-seq data) of the cortex, hippocampus, and cerebellum of 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 on 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 activation of tau protein hyperphosphorylation and beta-amyloid depositions. Moreover, the acetylcholinergic system is deficient in the background of hyperactivation of acetylcholinesterase. Importantly, the activity of the dopaminergic, endorphin, and opiate systems in OBX mice decreases leading to hormonal dysfunction. Genes responsible for the regulation of circadian rhythms, cell migration, and impaired innate immunity are activated in OBX animals. All this takes place on the background of drastic down-regulation 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. This model can be tentatively attributed to AD subtype B2 in humans.