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Intranasal Administration of Hsp70: Molecular and Therapeutic Consequences

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HSP70 in Human Diseases and Disorders

Part of the book series: Heat Shock Proteins ((HESP,volume 14))

Abstract

Hsp70 and other molecular chaperones function as a complex neuroprotective system, which fails in the brains of aged people and Alzheimer’s disease (AD)-type neuropathologies. It was demonstrated that intranasally injected exogenous Hsp70 (eHsp70) effectively bypassed the blood-brain barrier and penetrates brain regions of the model animals. It was shown that chronic administration of eHsp70 decreases beta-amyloid level and the number of Aβ-plaques in two mouse models of AD. In both cases eHsp70 restored learning and memory parameters as well as functional state of neurons. Characteristically, eHsp70 treatment increased synaptophysin level and protects neurons in brain areas most affected in AD patients such as hippocampus and neocortex. It was also demonstrated that eHsp70 can promote longevity and life quality in male mice. The eHsp70 treatment decreased accumulation of aging marker lipofuscin and modulates the activity of UPS by increasing expression of several proteasome subunits including immunoproteasome subunit β5i. Deep sequencing studies exploring brain regions of AD-model – 5XFAD mice treated with eHsp70 revealed candidate genes and signal pathways probably underlying beneficial effects of eHsp70 treatment. Taken together, our findings establish intranasal administration of exogenous human Hsp70 as a practical therapeutic approach for the treatment of various neurodegenerative diseases and aging.

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Abbreviations

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

BAG:

Bcl-2-associated athanogene-1

BBB:

Blood-brain barrier

BSA:

Bovine serum albumin

CHIP:

Carboxy-terminus of Hsc70-interacting protein

CNS:

Central nervous system

Hsp:

Heat shock protein

LPS:

Lipopolysaccharide

LTA:

Lipoteichoic acid

NMDA:

N-methyl-D-aspartate receptor

PTZ:

Pentylenetetrazole

ROS:

Reactive oxygen species

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

UPS:

Ubiquitin-proteasome system

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Acknowledgments

The work was supported by Russian Science Foundation Grant №14-50-00060 and Program of fundamental research for state academies for 2013-2020 years (N-01201363817).

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Authors and Affiliations

  1. Engelhardt Institute of Molecular Biology, Moscow, Russia

    Michael B. Evgen’ev, David G. Garbuz & Alexei V. Morozov

  2. Institute of Cell Biophysics, RAS, Moscow, Russia

    Michael B. Evgen’ev & Natalia V. Bobkova

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  1. Michael B. Evgen’ev
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  2. David G. Garbuz
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  3. Alexei V. Morozov
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  4. Natalia V. Bobkova
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Editors and Affiliations

  1. Department of Medicine and Precision Therapeutics Proteogenomics Diagnostic Center, Eleanor N. Dana Cancer Center, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA

    Alexzander A. A. Asea

  2. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Punit Kaur

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Evgen’ev, M.B., Garbuz, D.G., Morozov, A.V., Bobkova, N.V. (2018). Intranasal Administration of Hsp70: Molecular and Therapeutic Consequences. In: Asea, A., Kaur, P. (eds) HSP70 in Human Diseases and Disorders. Heat Shock Proteins, vol 14. Springer, Cham. https://doi.org/10.1007/978-3-319-89551-2_16

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