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Brain Behav Immun. 2017 Nov;66:347-358. doi: 10.1016/j.bbi.2017.07.158. Epub 2017 Jul 29.

Protection against RAGE-mediated neuronal cell death by sRAGE-secreting human mesenchymal stem cells in 5xFAD transgenic mouse model.

Author information

1
Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon, Republic of Korea; Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
2
Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
3
Department of Biochemistry and Cell Biology, Kyungpook National University, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
4
Department of Medicine, University of British Columbia, Vancouver, Canada.
5
Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon, Republic of Korea; Center for Regenerative Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea. Electronic address: bhlee@gachon.ac.kr.
6
Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon, Republic of Korea; Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea. Electronic address: khbyun1@gachon.ac.kr.

Abstract

Alzheimer's disease (AD), which is the most commonly encountered neurodegenerative disease, causes synaptic dysfunction and neuronal loss due to various pathological processes that include tau abnormality and amyloid beta (Aβ) accumulation. Aβ stimulates the secretion and the synthesis of Receptor for Advanced Glycation End products (RAGE) ligand by activating microglial cells, and has been reported to cause neuronal cell death in Aβ1-42 treated rats and in mice with neurotoxin-induced Parkinson's disease. The soluble form of RAGE (sRAGE) is known to reduce inflammation, and to decrease microglial cell activation and Aβ deposition, and thus, it protects from neuronal cell death in AD. However, sRAGE protein has too a short half-life for therapeutic purposes. We developed sRAGE-secreting umbilical cord derived mesenchymal stem cells (sRAGE-MSCs) to enhance the inhibitory effects of sRAGE on Aβ deposition and to reduce the secretion and synthesis of RAGE ligands in 5xFAD mice. In addition, these cells improved the viability of injected MSCs, and enhanced the protective effects of sRAGE by inhibiting the binding of RAGE and RAGE ligands in 5xFAD mice. These findings suggest sRAGE protein from sRAGE-MSCs has better protection against neuronal cell death than sRAGE protein or single MSC treatment by inhibiting the RAGE cell death cascade and RAGE-induce inflammation.

KEYWORDS:

5xFAD; Alzheimer’s disease; Human UC-MSCs; Neuronal cell death; RAGE pathway; Soluble RAGE

PMID:
28760504
DOI:
10.1016/j.bbi.2017.07.158
[Indexed for MEDLINE]

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