title: Administrations of human adult ischemia-tolerant mesenchymal stem cells and factors reduce amyloid beta pathology in a mouse model of Alzheimer's disease.
abstract: The impact of human adult ischemia-tolerant mesenchymal stem cells (hMSCs) and factors (stem cell factors) on cerebral amyloid beta (Aβ) pathology was investigated in a mouse model of Alzheimer's disease (AD). To this end, hMSCs were administered intravenously to APPPS1 transgenic mice that normally develop cerebral Aβ. Quantitative reverse transcriptase polymerase chain reaction biodistribution revealed that intravenously delivered hMSCs were readily detected in APPPS1 brains 1 hour following administration, and dropped to negligible levels after 1 week. Notably, intravenously injected hMSCs that migrated to the brain region were localized in the cerebrovasculature, but they also could be observed in the brain parenchyma particularly in the hippocampus, as revealed by immunohistochemistry. A single hMSC injection markedly reduced soluble cerebral Aβ levels in APPPS1 mice after 1 week, although increasing several Aβ-degrading enzymes and modulating a panel of cerebral cytokines, suggesting an amyloid-degrading and anti-inflammatory impact of hMSCs. Furthermore, 10 weeks of hMSC treatment significantly reduced cerebral Aβ plaques and neuroinflammation in APPPS1 mice, without increasing cerebral amyloid angiopathy or microhemorrhages. Notably, a repeated intranasal delivery of soluble factors secreted by hMSCs in culture, in the absence of intravenous hMSC injection, was also sufficient to diminish cerebral amyloidosis in the mice. In conclusion, this preclinical study strongly underlines that cerebral amyloidosis is amenable to therapeutic intervention based on peripheral applications of hMSC or hMSC factors, paving the way for a novel therapy for Aβ amyloidosis and associated pathologies observed in AD.
authors.affiliation: Laboratoire d'optique Biomédicale, School of Engineering, Ecole Polytechnique fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Taoufiq
authors.initials: T
authors.lastname: Harach
authors.affiliation: Laboratoire d'optique Biomédicale, School of Engineering, Ecole Polytechnique fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Fabien
authors.initials: F
authors.lastname: Jammes
authors.affiliation: Stemedica International, Lausanne, Switzerland.
authors.forename: Charles
authors.initials: C
authors.lastname: Muller
authors.affiliation: Laboratoire d'optique Biomédicale, School of Engineering, Ecole Polytechnique fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Duthilleul
authors.affiliation: Laboratoire d'optique Biomédicale, School of Engineering, Ecole Polytechnique fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Victoria
authors.initials: V
authors.lastname: Cheatham
authors.affiliation: Laboratoire d'optique Biomédicale, School of Engineering, Ecole Polytechnique fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Valentin
authors.initials: V
authors.lastname: Zufferey
authors.affiliation: Stemedica International, Lausanne, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Cheatham
authors.affiliation: Laboratoire d'optique Biomédicale, School of Engineering, Ecole Polytechnique fédérale de Lausanne, Lausanne, Switzerland; Stemedica International, Lausanne, Switzerland.
authors.forename: Yelizaveta A
authors.initials: YA
authors.lastname: Lukasheva
authors.affiliation: Laboratoire d'optique Biomédicale, School of Engineering, Ecole Polytechnique fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Theo
authors.initials: T
authors.lastname: Lasser
authors.affiliation: Laboratoire d'optique Biomédicale, School of Engineering, Ecole Polytechnique fédérale de Lausanne, Lausanne, Switzerland; Stemedica International, Lausanne, Switzerland. Electronic address: tristan.bolmont@epfl.ch.
authors.forename: Tristan
authors.initials: T
authors.lastname: Bolmont
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007275:Injections, Intravenous; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D018836:Inflammation Mediators
keywords: Alzheimer's disease; Cerebral Abeta amyloidosis; Human adult ischemia-tolerant mesenchymal stem cells; Intranasal application; Intravenous delivery; Stem cell factors; Transgenic mice