Protective effects of two different chaperones demonstrated in a mouse model of sporadic AD
Previously, using various animal models of AD, we demonstrated the protective effect of intranasal administration of chaperones of such different structure as HSP70 and YB-1 at the level of animal's behavior and functional state and morphology of different brain regions. We also described transcriptional changes in the brain of mice after bulbectomy (OBX mice) representing a model of sporadic AD with elements of major depression. Herein, we investigated the effects of recombinant HSP70 and YB1 sub-chronic administration on transcription in the hippocampus and cortex of the OBX mice. Both chaperones introduction caused significant changes in the transcription of the studied brain regions, partially reverting it to a pattern of the control sham operated mice. More than 60% of genes with altered transcription levels due to bulbectomy exhibited complete restoration of their normal expression levels after both chaperones treatment. Importantly, the number of genes with altered expression after chaperones treatment was twice as high in the hippocampus as in the cortex. The administration of the chaperones led to complete or partial normalization of the expression of many genes related to the metabolism of beta-amyloid and tau protein in the brain of OBX mice. Thus, both proteins reduced the expression of genes such as Kmt2d, Apba, Casp9, Sorl1, Ywhag, Ywhaz and others, that increased expression as a result of bulbectomy and in parallel compensatory increased the expression of such genes as Prepl, Pfdn2, Fbxl16, Nsf etc. Both chaperones normalized the expression of many genes involved in rRNA processing and ribosome biogenesis, as well as genes involved in the processes of neurotransmitter transport and secretion, cognition, apoptosis, ferroptosis and mitochondrial regulation. Thus, both chaperones normalized the expression of 47 genes involved in mitochondria function, including the expression of the Pet117 gene, responsible for the rate of oxygen consumption by mitochondria and the expression of Mgst1  gene which affects the protection of mitochondria from oxidative stress. Importantly, administration of YB-1 and Hsp70 normalized the expression of a number of genes involved in the formation of the cytoskeleton. A significant compensatory effect of both chaperones was demonstrated in all six cell types studied in the brain of OBX mice with the most pronounced effect observed in the astrocytes. Notably, besides genes specific for AD, administration of both proteins normalized the expression of a few genes specific for major depression altered in OBX mice and several genes implicated in the development of other neurodegenerative diseases. Overall design: Single end polyA RNA-sequencing of brain tissues of mouse undergone olfactory bulbectomy after treatment with HSP70 or YB-1 proteins