title: Replacement of microglial cells using Clodronate liposome and bone marrow transplantation in the central nervous system of SOD1(G93A) transgenic mice as an in vivo model of amyotrophic lateral sclerosis.
abstract: Disease progression of amyotrophic lateral sclerosis (ALS) is partially mediated by the toxic microenvironment established by microglia. In the present study, we used SOD1G93A transgenic mice as an in vivo ALS model and replaced microglia expressing mutant SOD1 (mSOD1) with microglia expressing wild-type SOD1 (w/tSOD1) to modulate the toxic microenvironment. Stereotactic injection of Clodronate liposome, a selective toxin against the monocyte/macrophage system, into the fourth ventricle of the brains of 12-week-old asymptomatic ALS mice reduced the number of microglia effectively in the central nervous system. Subsequent bone marrow transplantation (BMT) with bone marrow cells (BMCs) expressing w/tSOD1 and GFP leads to replacement of the endogenous microglia of the ALS mice with microglia expressing w/tSOD1 and GFP. The expression of mSOD1 in the other neural cells was not influenced by the replacement procedures, and immunological side effects were not observed. The replacement of microglia significantly slowed disease progression and prolonged survival of the ALS mice compared with the ALS mice treated by stereotactic injection of PBS-liposome and BMT with BMCs expressing mSOD1 or w/tSOD1. These results suggest that replacement of microglia would improve the neural cell microenvironment, thereby slowing disease progression. The mechanisms and functional implications of this replacement require further elucidation.
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-799, Republic of Korea.
authors.forename: Jae Chul
authors.initials: JC
authors.lastname: Lee
authors.forename: Jinsil
authors.initials: J
authors.lastname: Seong
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Se Jeong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Cho
authors.forename: Jaeyeol
authors.initials: J
authors.lastname: An
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.forename: Choong Ik
authors.initials: CI
authors.lastname: Cha
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000818:Animals; D016026:Bone Marrow Transplantation; D002490:Central Nervous System / Q000201:enzymology* / Q000473:pathology; D004002:Clodronic Acid / Q000008:administration & dosage*; D004195:Disease Models, Animal; D007276:Injections, Intraventricular; D008081:Liposomes; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009154:Mutation; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D008081:Liposomes; D004002:Clodronic Acid; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1