title: Phenotypic transition of microglia into astrocyte-like cells associated with disease onset in a model of inherited ALS.
abstract: Microglia and reactive astrocytes accumulate in the spinal cord of rats expressing the Amyotrophic lateral sclerosis (ALS)-linked SOD1 (G93A) mutation. We previously reported that the rapid progression of paralysis in ALS rats is associated with the appearance of proliferative astrocyte-like cells that surround motor neurons. These cells, designated as Aberrant Astrocytes (AbA cells) because of their atypical astrocytic phenotype, exhibit high toxicity to motor neurons. However, the cellular origin of AbA cells remains unknown. Because AbA cells are labeled with the proliferation marker Ki67, we analyzed the phenotypic makers of proliferating glial cells that surround motor neurons by immunohistochemistry. The number of Ki67 (+)AbA cells sharply increased in symptomatic rats, displaying large cell bodies with processes embracing motor neurons. Most were co-labeled with astrocytic marker GFAP concurrently with the microglial markers Iba1 and CD163. Cultures of spinal cord prepared from symptomatic SOD1 (G93A) rats yielded large numbers of microglia expressing Iba1, CD11b, and CD68. Cells sorted for CD11b expression by flow cytometry transformed into AbA cells within two weeks. During these two weeks, the expression of microglial markers largely disappeared, while GFAP and S100β expression increased. The phenotypic transition to AbA cells was stimulated by forskolin. These findings provide evidence for a subpopulation of proliferating microglial cells in SOD1 (G93A) rats that undergo a phenotypic transition into AbA cells after onset of paralysis that may promote the fulminant disease progression. These cells could be a therapeutic target for slowing paralysis progression in ALS.
authors.affiliation: Instituto de Investigaciones Biológicas Clemente Estable Montevideo, Uruguay.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Trias
authors.affiliation: Instituto de Investigaciones Biológicas Clemente Estable Montevideo, Uruguay.
authors.forename: Pablo
authors.initials: P
authors.lastname: Díaz-Amarilla
authors.affiliation: Instituto de Investigaciones Biológicas Clemente Estable Montevideo, Uruguay.
authors.forename: Silvia
authors.initials: S
authors.lastname: Olivera-Bravo
authors.affiliation: Instituto de Investigaciones Biológicas Clemente Estable Montevideo, Uruguay.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Isasi
authors.affiliation: Department of Biochemistry and Biophysics, Oregon State University Corvallis, OR, USA ; Environmental Health Sciences Center, Oregon State University, Corvallis OR, USA.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Drechsel
authors.affiliation: Department of Biochemistry and Biophysics, Oregon State University Corvallis, OR, USA ; Environmental Health Sciences Center, Oregon State University, Corvallis OR, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Lopez
authors.affiliation: Department of Biochemistry and Biophysics, Oregon State University Corvallis, OR, USA ; Environmental Health Sciences Center, Oregon State University, Corvallis OR, USA.
authors.forename: C Samuel
authors.initials: CS
authors.lastname: Bradford
authors.affiliation: Department of Biochemistry and Biophysics, Oregon State University Corvallis, OR, USA ; Environmental Health Sciences Center, Oregon State University, Corvallis OR, USA ; Institut Pasteur de Montevideo Montevideo, Uruguay.
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Ireton
authors.affiliation: Department of Biochemistry and Biophysics, Oregon State University Corvallis, OR, USA ; Environmental Health Sciences Center, Oregon State University, Corvallis OR, USA ; Linus Pauling Institute, Oregon State University Corvallis, OR, USA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Beckman
authors.affiliation: Institut Pasteur de Montevideo Montevideo, Uruguay.
authors.forename: Luis
authors.initials: L
authors.lastname: Barbeito
keywords: ALS; AbA cells; astrocytes; microglia; neurodegeneration; phenotypic transformation