Heterogeneity of Neuroinflammatory Responses in Amyotrophic Lateral Sclerosis: A Challenge or an Opportunity?

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a complex pathology: (i) the neurodegeneration is chronic and progressive; it starts focally in specific central nervous system (CNS) areas and spreads to different districts; (ii) multiple cell types further than motor neurons (i.e., glial/immune system cells) are actively involved in the disease; (iii) both neurosupportive and neurotoxic neuroinflammatory responses were identified. Microglia cells (a key player of neuroinflammation in the CNS) attracted great interest as potential target cell population that could be modulated to counteract disease progression, at least in preclinical ALS models. However, the heterogeneous/multifaceted microglia cell responses occurring in different CNS districts during the disease represent a hurdle for clinical translation of single-drug therapies. To address this issue, over the past ten years, several studies attempted to dissect the complexity of microglia responses in ALS. In this review, we shall summarize these results highlighting how the heterogeneous signature displayed by ALS microglia reflects not only the extent of neuronal demise in different regions of the CNS, but also variable engagement in the attempts to cope with the neuronal damage. We shall discuss novel avenues opened by the advent of single-cell and spatial transcriptomics technologies, underlining the potential for discovery of novel therapeutic targets, as well as more specific diagnostic/prognostic not-invasive markers of neuroinflammation.

Keywords: PET; microglia; neuroinflammation; single-cell RNAseq; spatial transcriptomics.

Figure 1

Amyotrophic Lateral Sclerosis (ALS) is a complex pathology. There is variability in the extent of neuronal demise in different central nervous system (CNS) districts affected by the disease. This leads to heterogeneity of neuroinflammatory (microglia) responses, characterized by variable engagement in the attempt to cope with neuronal demise.

Figure 2

Strategies to investigate the complex microglia signature in ALS include single-cell and spatial transcriptomics approaches or multi-omics techniques such as cytofluorometry by time-of-flight (CyTOF). These will allow to identify novel targets that could be exploited therapeutically or for magnetic resonance imaging (MRI)/positron emission tomography (PET) imaging studies.