Drechsel, Derek A.
Bradford, C. Samuel
Ireton, Kyle E.
Beckman, Joseph S.
- Microglia and reactive astrocytes accumulate in the spinal cord of rats expressing the Amyotrophic
lateral sclerosis (ALS)-linked SOD1ᴳ⁹³ᴬ mutation. We previously reported that the rapid progression
of paralysis in ALS rats is associated with the appearance of prolifer- ative 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 SOD1ᴳ⁹³ᴬ 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
SOD1ᴳ⁹³ᴬ 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.
- Trias, E., Díaz-Amarilla, P., Olivera-Bravo, S., Isasi, E., Drechsel, D. A., Lopez, N., ... & Barbeito, L. (2013). Phenotypic transition of microglia into astrocyte-like cells associated with disease onset in a model of inherited ALS. Frontiers in Cellular Neuroscience, 7. doi:10.3389/fncel.2013.00274
|Funding Statement (additional comments about funding)
- National Center for Complementary and Alternative Medicine Grant NCCAM P01AT002034
- FOCEM-Mercosur funding
- ALS Association
- Program for development of basic sciences (PEDECIBA)
- Innovation and Research National Agency (ANII)
- National Institute on Environmental Health Sciences Grant P30ES000210
- National Institute of Neurological Disorders and Stroke Grant R01NS058628A
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