Astrocyte regional diversity in ALS includes distinct aberrant phenotypes with common and causal pathological processes

Glia-Derived Extracellular Vesicles: Role in Central Nervous System Communication in Health and Disease

“…However, assessing the impact of astrocytes on the inflammatory conditions of neurodegenerative diseases is not easy, as regional diversity may exist, as suggested by a recent work on amyotrophic lateral sclerosis (ALS) (Gomes et al, 2020). ALS is a neurodegenerative disorder in which astrocytes are important players for motor neuron loss in both brain cortex and spinal cord.…”

“…ALS is a neurodegenerative disorder in which astrocytes are important players for motor neuron loss in both brain cortex and spinal cord. The authors showed that the inflammation-related miRNAs miR-155, miR-21 and miR-146a are downregulated in primary cortical astrocytes from mSOD1 mice but upregulated in spinal cord astrocytes (Gomes et al, 2020). Interestingly, a reduction of these miRNAs was reported in the EVs from both cortical and spinal cord astrocytes, suggesting the need to assess the impact of astrocyte-derived EVs in ALS-related neuroinflammatory processes.…”

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“…Astrocytes isolated from the SC of symptomatic rats exhibit low levels of glial fibrillary acidic protein (GFAP) and glutamate transporter 1 (GLT-1), together with increased S100B and Cx43, and were designated as aberrant astrocytes (Díaz-Amarilla et al, 2011). We lately confirmed this same set of aberrant/reactive markers in astrocytes isolated from the SOD1G93A (mSOD1) mice at 7-day-old and cultured for 13 days in vitro (DIV) (Gomes et al, 2019;Gomes et al, 2020), pointing that such astrocytes acquire early deficits associated to a disease-specific phenotype, including low levels of GFAP. These low levels of GFAP were also found in other harmful conditions (Escartin et al, 2021).…”

“…This model is well characterized in terms of behavior, histopathology, and molecular mechanisms, and recapitulates most of the pathological features of the human ALS (Al-Chalabi et al, 2017). Although motor neuron (MN) loss is believed to be the predominant feature, astrogliosis has a key role in MN degeneration due to the release of unknown toxic factors, either in the brain cortex or in the spinal cord (SC) (Robberecht and Philips, 2013;Gomes et al, 2020), and in both sporadic ALS (sALS) (Varga et al, 2018) and familiar ALS (fALS) (Meyer et al, 2014;van Rheenen et al, 2016).…”

“…We previously found that the aberrant mSOD1 cortical astrocytes expressed reduced levels of miR-146a (Gomes et al, 2019). We also identified reduced levels of miR-146a in sEVs released from both cortical and spinal 13 DIV astrocytes that when cocultured with MNs showed to determine several dysfunctionalities (Gomes et al, 2020). We then wonder whether such depleted levels of miR-146a in mSOD1 astrocytes and their sEVs could relate with the cell pathological features and have harmful consequences to nearby MNs and microglia.…”