Microglia May Turn Astrocytes to the Dark Side in ALS

The death star? Astrocytes support motor neurons by nourishing them. But in patients with ALS, some of these cells might turn against motor neurons and destroy them. [Courtesy of Shane Liddelow, Stanford University School of Medicine. Reproduced with permission. All rights reserved.]

Microglia may turn some astrocytes against motor neurons and oligodendrocytes in ALS according to a study published on January 18 in Nature. The study, led by Ben Barres of Stanford University School of Medicine, found that a subset of astrocytes appeared to proliferate upon neuronal injury in vivo leading to degeneration of more than 60% of nearby neurons. What’s more, these cells appeared to inhibit the differentiation and proliferation of oligodendrocyte precursor cells (OPCs) and destroy oligodendrocytes, key cells that provide metabolic support to motor neurons that appear to be lost in the disease (see January 2011, April 2013 and November 2016 news; Lee et al., 2013). This astroglial about-face appeared to be instigated by reactive microglia due to the secretion of interleukin-1α, tumor necrosis factor (TNF) and complement C1q. The cells, called A1 astrocytes, could be detected in post mortem tissue from patients with five neurodegenerative diseases including ALS. The results suggest that this microglial-based attack strategy could be a key general underlying mechanism of neurodegenerative disease (see January 2017 news).

Researchers first suspected in 2011 that some astrocytes might go rogue in ALS by studying the G93A rat model of SOD1 disease. The study, led by Luis Barbeito at the Institut Pasteur de Montevideo in Uruguay, found that a subset of astrocyte-like cells appeared in the ventral horn of the spinal cord during symptom onset – surrounding damaged motor neurons. In addition, the numbers of these cells rose during disease progression – increasing more than 50% by the end stage of the disease. The cells, called aberrant astrocytes (ABAs), appeared to destroy motor neurons by secreting neurotoxic substances including connexin 43 – at least in culture.

Together, the results suggest these astrocytes may be a key contributor to ALS and targeting them may be a potential therapeutic strategy for the disease.

Read more:

Microglia Give Astrocytes the License to Kill

In ALS Astrocytes, Upregulated Connexins Contribute to Motor Neuron Death

References:

Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017 Jan 26;541(7638):481-487. [PubMed].

Díaz-Amarilla P, Olivera-Bravo S, Trias E, Cragnolini A, Martínez-Palma L, Cassina P, Beckman J, Barbeito L. (2011) Phenotypically aberrant astrocytes that promote motoneuron damage in a model of inherited amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18126-31. [PubMed].

Further Reading

Almad AA, Doreswamy A, Gross SK, Richard JP, Huo Y, Haughey N, Maragakis NJ. Connexin 43 in astrocytes contributes to motor neuron toxicity in amyotrophic lateral sclerosis. Glia. 2016 Jul;64(7):1154-1169. [PubMed]

astrocyte disease-als microglia topic-preclinical topic-researchmodels
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