Neuroinflammation and ALS: Transcriptomic Insights into Molecular Disease Mechanisms and Therapeutic Targets

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system. Despite the mechanism underlying motor neuron death is not yet clarified, multiple pathogenic processes have been proposed to account for ALS. Among these, inflammatory/immune responses have recently gained particular interest, although there are conflicting reports on the role of these processes in ALS pathogenesis and treatment. This apparent discrepancy may be due to the absence of an effective stratification of ALS patients into subgroups with markedly different clinical, biological, and molecular features. Our research group recently described genome-wide characterization of motor cortex samples from sporadic ALS (SALS) patients, revealing the existence of molecular and functional heterogeneity in SALS. Here, we reexamine data coming from our previous work, focusing on transcriptomic changes of inflammatory-related genes, in order to investigate their potential contribution in ALS. A total of 1573 inflammatory genes were identified as differentially expressed between SALS patients and controls, characterizing distinct topological pathways and networks, suggestive of specific inflammatory molecular signatures for different patient subgroups. Besides providing promising insights into the intricate relationship between inflammation and ALS, this paper represents a starting point for the rationale design and development of novel and more effective diagnostic and therapeutic applications.

Neuro‐Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice

“…The findings concerning Iba‐1 and GSK‐3ß expression support the view that there is a critical role for microglial activation and inflammation in ALS . The upregulation of GSK‐3ß cascade is known to be functionally associated with pro‐inflammatory changes and microglial activation, which is a well‐established marker of ALS histopathology, and the FUS‐ALS forms in particular .…”

“…Regardless of whether the disease is associated with FUS gene mutations or related to other factors, its pathological mechanisms are associated with neuroinflammation . In particular, the activation of microglia and astrocytes is considered to be a hallmark of the disease and is accompanied by elevated pro‐inflammatory cytokine concentrations in the brain, blood, and cerebrospinal fluid .…”

“…Regardless of whether the disease is associated with FUS gene mutations or related to other factors, its pathological mechanisms are associated with neuroinflammation . In particular, the activation of microglia and astrocytes is considered to be a hallmark of the disease and is accompanied by elevated pro‐inflammatory cytokine concentrations in the brain, blood, and cerebrospinal fluid . For example, a recent clinical study reported high blood concentrations of pro‐inflammatory cytokines and related proteins in ALS patients, including interleukin‐1β (IL‐1β), interleukin 6 (IL‐6), interleukin‐8 (IL‐8), tumor necrosis factor (TNF), and TNF receptor‐1 .…”

“…For example, a recent clinical study reported high blood concentrations of pro‐inflammatory cytokines and related proteins in ALS patients, including interleukin‐1β (IL‐1β), interleukin 6 (IL‐6), interleukin‐8 (IL‐8), tumor necrosis factor (TNF), and TNF receptor‐1 . It has been suggested that microglial inflammatory processes might be a key early event that contribute to neurodegeneration and play a dynamic role in the pathogenesis of the disease . Cerebrospinal fluid from ALS patients induces marked microglial activation, and upregulation of the pro‐inflammatory cytokines and factors including IL‐6, TNF, cyclooxygenase‐2 (COX‐2), and prostaglandin E2 (PGE2), accompanied by a downregulation of trophic factors …”

Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail?

“…Also, in patients suffering from chronic neurodegenerative disorders, Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis (ALS) inclusive, antiinflammatory drugs were found to be ineffective (Fondell et al 2012;Collins and Bowser 2017;Khalid et al 2017;Crisafulli et al 2018). Activation of microglia and astrocytes with increased levels of pro-inflammatory serum and CSF cytokines IL-1β, IL-6, IL-8, TNF and vascular endothelial growth factor (VEGF) is considered the hallmark in ALS (Ciervo et al 2017;Hu et al 2017;Morello et al 2017;Crisafulli et al 2018). Interventions with corticosteroids and/or other anti-inflammatory drugs such as the COX-2 inhibitor celecoxib, which causes the reduction of the brain levels of inflammatory cytokines TNF and IL-1β (Osman et al 2016), however, were found ineffective in experimental ALS-like animals and/or ALS patients (Galbiati et al 2012;Collins and Bowser 2017;Crisafulli et al 2018).…”