Molecular mechanisms underlying neuroprotective effect of exogenous Hsp70 in aging and transgenic 5XFAD mice

Heat shock protein 70, in humans encoded by the HSPA1A gene, is a key component of the machinery protecting the neuronal cells from various stress conditions whose production significantly declines in the course of aging. Herein, we investigated the protective effect of sub-chronic intranasal administration of exogenous Hsp70 on the state of neurons in the temporal cortex and areas of hippocampus of wild type and transgenic 5XFAD mice (model of Alzheimer’s disease) belonging to different age groups. The quantitative analysis of various pathologies in the compared groups revealed maximal level of abnormalities in brains of aged transgenic mice. Importantly, Hsp70 treatment had the most profound beneficial effect on neuron morphology and functional state especially in the hippocampal regions when applied to the aged transgenic mice. Hsp70 administration has clear-cut rejuvenation effect on the functional state of neurons when applied to non-transgenic aged mice as well. Similarly, the beneficial effect of the addition of eHsp70 to primary hippocampal cultures of 5XFAD animals strongly depends on the age of the cultures.Using deep sequencing we identified multiple differentially expressed genes (DEGs) in the hippocampus of compared transgenic and non-transgenic mice belonging to different age groups. Furthermore, the performed analysis demonstrated that intranasal application of eHsp70 strongly modulates the spectrum of DEGs in aged transgenic animals making it similar to that of non-transgenic age-matched mice. Overall, our data enable to conclude that Hsp70 treatment may be a safe and effective therapeutic against neuropathologies of Alzheimer type.