Molecular Mechanisms Underlying Neuroprotective Effect of Intranasal Administration of Human Hsp70 in Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: Evgen’ev, Michail B.^{a; b; *} | Krasnov, George S.^a | Nesterova, Inna V.^b | Garbuz, David G.^a | Karpov, Vadim L.^a | Morozov, Alexey V.^a | Snezhkina, Anastasiya V.^a | Samokhin, Alexander N.^b | Sergeev, Alexander^b | Kulikov, Alexei M.^c | Bobkova, Natalia V.^b

Affiliations: [a] Engelhardt Institute of Molecular Biology, Moscow, Russia | [b] Institute of Cell Biophysics, RAS, Pushchino, Moscow region, Russia | [c] Institute of Developmental Biology, Moscow, Russia

Correspondence: [*] Correspondence to: Michail B. Evgen’ev, Engelhardt Institute of Molecular Biology, Vavilov str. 32, Moscow 119991, Russia. Tel.: +7 4991359768; E-mail: [email protected].

Abstract: Heat shock protein 70, encoded by the HSPA1A gene in humans, is a key component of the machinery that protects neuronal cells from various stress conditions and whose production significantly declines during the course of aging and as a result of several neurodegenerative diseases. Herein, we investigated whether sub-chronic intranasal administration of exogenous Hsp70 (eHsp70) exerts a neuroprotective effect on the temporal cortex and areas of the hippocampus in transgenic 5XFAD mice, a model of Alzheimer’s disease. The quantitative analysis of neuronal pathologies in the compared groups, transgenic (Tg) versus non-transgenic (nTg), revealed high level of abnormalities in the brains of transgenic mice. Treatment with human recombinant Hsp70 had profound rejuvenation effect on both neuronal morphology and functional state in the temporal cortex and hippocampal regions in transgenic mice. Hsp70 administration had a smaller, but still significant, effect on the functional state of neurons in non-transgenic mice as well. Using deep sequencing, we identified multiple differentially expressed genes (DEGs) in the hippocampus of transgenic and non-transgenic mice. Furthermore, this analysis demonstrated that eHsp70 administration strongly modulates the spectrum of DEGs in transgenic animals, reverting to a pattern similar to that observed in non-transgenic age-matched mice, which included upregulation of genes responsible for amine transport, transmission of nerve impulses and other pathways that are impaired in 5XFAD mice. Overall, our data indicate that Hsp70 treatment may be an effective therapeutic against old age diseases of the Alzheimer’s type.

Keywords: 5XFAD mice, hippocampus, neuronal pathology, recombinant Hsp70, transcriptome

DOI: 10.3233/JAD-170398

Journal: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1415-1426, 2017