The Microglial Component of Amyotrophic Lateral Sclerosis

Benjamin E. Clarke; Rickie Patani


Brain. 2020;143(12):3526-3539. 

In This Article

Abstract and Introduction


Microglia are the primary immune cells of the CNS, carrying out key homeostatic roles and undergoing context-dependent and temporally regulated changes in response to injury and neurodegenerative diseases. Microglia have been implicated in playing a role in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by extensive motor neuron loss leading to paralysis and premature death. However, as the pathomechansims of ALS are increasingly recognized to involve a multitude of different cell types, it has been difficult to delineate the specific contribution of microglia to disease. Here, we review the literature of microglial involvement in ALS and discuss the evidence for the neurotoxic and neuroprotective pathways that have been attributed to microglia in this disease. We also discuss accumulating evidence for spatiotemporal regulation of microglial activation in this context. A deeper understanding of the role of microglia in the 'cellular phase' of ALS is crucial in the development of mechanistically rationalized therapies.


Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease involving the degeneration of both upper and lower motor neurons in the motor cortex, brainstem and spinal cord (Al-Chalabi et al., 2017). Loss of motor neurons results in extensive paralysis commencing usually focally in the limbs or bulbar muscles. ALS is a universally fatal disease, typically due to respiratory failure between 2 and 5 years after diagnosis (Niedermeyer et al., 2019). Most cases of ALS (>90%) are sporadic, but study of familial forms of the disease has been critical in identifying causative mutations, now numbering more than 30 genes. Mutations in C9orf72, SOD1, TARDBP and FUS are the most common genetic forms, accounting for more than half of familial ALS cases. Although motor neurons are primarily affected in ALS, non-neuronal cells play a key role in disease progression (Philips and Rothstein, 2014; Beers and Appel, 2019). Motor neuron death itself, and the pathogenic cascade within surviving motor neurons, are accompanied by an inflammatory response. Evidence for this from blood and CSF of ALS patients is well established (Tateishi et al., 2010; Gupta et al., 2011; Lu et al., 2016). This includes the activation of CNS resident microglia and astrocytes. Here, we will focus primarily on the microglial contribution to ALS, before discussing cellular interplay with motor neurons, astrocytes, oligodendrocytes and peripheral immune cells invading the CNS. It is clear that neurodegeneration can trigger inflammation and that inflammation itself can contribute to the process of neurodegeneration. The issue of whether inflammation might cause neurodegeneration in ALS remains unresolved. The finding of ALS-related gene mutations being expressed in microglia is consistent with a possible upstream role of neurodegeneration, but more work is required here to gain a more comprehensive insight (Cady et al., 2014).

Microglia are the primary immune cells of the CNS with critical roles in the protection of neurons from infection or injury and in synaptic regulation (Davalos et al., 2005; Nimmerjahn et al., 2005; Schafer et al., 2013). Unlike other resident cells of the CNS, microglia do not originate from the ectoderm and instead arise from primitive macrophages in the mesodermal yolk sac, invading the CNS during development (Ginhoux et al., 2010). Microglial identity is thought to manifest through both an ontological basis and refinement by local CNS cues (Bennett et al., 2018). Significant brain regional heterogeneity of mouse (Nikodemova et al., 2014; Grabert et al., 2016) and human (Böttcher et al., 2019) microglia has been reported, with recent single cell studies suggesting that this diversity is far higher in younger mice and in ageing/disease states than during normal adulthood (Ajami et al., 2018; Hammond et al., 2019; Li et al., 2019). Microglia are highly motile cells that constantly survey their micro-environment by continuously extending and retracting their processes, phagocytosing dead cells and debris. In response to a multitude of stimuli, microglia can become activated, undergoing graded and temporal changes in their morphology and gene expression in response to injury, infection or neurodegenerative diseases (Szalay et al., 2016; Mathys et al., 2017; Ajami et al., 2018; Hammond et al., 2019; Haruwaka et al., 2019). Microglia can also become proliferative when activated and release a wide variety of cytokines that have subsequent protective or detrimental effects on neurons (Li and Barres, 2018). The exact response of microglia to certain stimuli is context-dependent and may be determined by several factors including the chronicity of the stimulus, ageing and regional heterogeneity. Here, we review the literature specifically concerning the contribution of microglia to the pathological process of ALS.