Intravenously Injected Mesenchymal Stem Cells Penetrate the Brain and Treat Inflammation-Induced Brain Damage and Memory Impairment in Mice.

Olena Lykhmus,Serhiy Komisarenko,Kateryna Uspenska,Vitalii Kyryk,Nadia Shuvalova,Olena Deryabina,Vitalii Kordium,Maryna Skok,Larysa Voytenko,Lyudmyla Koval,Alina Ustymenko

doi:10.3389/fphar.2019.00355

Abstract

Neuroinflammation is regarded as one of the pathogenic factors of Alzheimer disease (AD). Previously, we showed that mice regularly injected with bacterial lipopolysaccharide (LPS) possessed the AD-like symptoms like episodic memory decline, elevated amounts of amyloid beta (Aβ) peptide (1–42), and decreased levels of nicotinic acetylcholine receptors (nAChRs) in the brain. The use of mesenchymal stem cells (MSCs), which can differentiate into multiple cell types, including neurons, is an attractive idea of regenerative medicine, in particular, for neurodegenerative disorders like AD. In the present study, we aimed to investigate whether pathogenic effect of LPS on the brain and behavior of mice can be prevented or treated by injection of MSCs or MSC-produced soluble factors. Fluorescently-labeled MSCs, injected intravenously, were found in the brain blood vessels of LPS-treated mice. Mice co-injected with LPS and MSCs did not demonstrate episodic memory impairment, Aβ (1–42) accumulation, and nAChR decrease in the brain and brain mitochondria. Their mitochondria released less cytochrome c under the effect of Ca2+ compared to mitochondria of LPS-only-treated mice. Moreover, MSCs could reverse the pathogenic symptoms developed 3 weeks after LPS injection. Cultured MSCs produced IL-6 in response to LPS and MSCs effect in vivo was accompanied by additional stimulation of both micro- and macroglia. Xenogeneic (human) MSCs were almost as efficient as allogeneic (mouse) ones and regular injections of human MSC-conditioned medium also produced positive effect. These data allow suggesting MSCs as a potential therapeutic tool to cure neuroinflammation-related cognitive pathology.

Highlights

Alzheimer disease (AD) is an age-dependent neurodegenerative disorder resulting in impairment of memory, speech, and practical habits
We studied a broader range of nicotinic acetylcholine receptor (nAChR) subunits in both the mitochondrial and nonmitochondrial brain fractions
The data obtained in the first set of experiments indicated that mesenchymal stem cells (MSCs) injected intravenously prevent the pathogenic effect of LPS on the brain, brain mitochondria and behavior of LPS-treated mice

Summary

Introduction

Alzheimer disease (AD) is an age-dependent neurodegenerative disorder resulting in impairment of memory, speech, and practical habits. The α4β2 nAChR signaling underlies the pro-cognitive effects of nicotine (Picciotto et al, 2001), the absence of α4β2 nAChRs in knockout mice favors neurodegeneration upon ageing (Zoli et al, 1999), and the density of α4β2 nAChRs is decreased in people with neurodegenerative diseases including the AD (Wevers et al, 1999; Guan et al, 2000). The α7 nAChRs directly interact with Aβ to affect its proper metabolism (Wang et al, 2000; Parri and Dineley, 2010). This nAChR subtype is expressed in both the plasma membrane and mitochondria of the brain cells to support their viability (Parada et al, 2010; Gergalova et al, 2012; Lykhmus et al, 2014). The α7 nAChRs expressed in the glial cells regulate inflammatory reactions in the brain (Suzuki et al, 2006; Tyagi et al, 2010; Thomsen and Mikkelsen, 2012)

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