Inflammation in ALS/FTD pathogenesis

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that overlap in their clinical presentation, pathology and genetics, and likely represent a spectrum of one underlying disease. In ALS/FTD patients, neuroinflammation characterized by innate immune responses of tissue-resident glial cells is uniformly present on end-stage pathology, and human imaging studies and rodent models support that neuroinflammation begins early in disease pathogenesis. Additionally, changes in circulating immune cell populations and cytokines are found in ALS/FTD patients, and there is evidence for an autoinflammatory state. However, despite the prominent role of neuro- and systemic inflammation in ALS/FTD, and experimental evidence in rodents that altering microglial function can mitigate pathology, therapeutic approaches to decrease inflammation have thus far failed to alter disease course in humans. Here, we review the characteristics of inflammation in ALS/FTD in both the nervous and peripheral immune systems. We further discuss evidence for direct influence on immune cell function by mutations in ALS/FTD genes including C9orf72, TBK1 and OPTN, and how this could lead to the altered innate immune system “tone” observed in these patients.

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

“…Unfortunately, monitoring inflammation by identifying microglia-produced cytokines as biomarkers to help in the diagnosis, to predict the progression, and to target key immune factors in the various neurodegenerative processes is still a challenge. The translation of cytokines as a biomarker in clinical practice is further hampered by intra-individual variation, environmental factors, genetic background, disease stage, and anatomical onset of motor neuron impairment (Hu et al 2017;McCauley and Baloh 2019;Moreno-Martinez et al 2019a, b). Even age and gender play a role, and the different pro-and anti-inflammatory cytokines along the disease progression, therefore, should be further studied to understand its time point activation and its relation to other molecular and clinical mediators in neurodegeneration to finally provide a better monitoring of disease progression (Moreno- Martinez et al 2019a).…”

Immune reactivity to neurofilaments and dipeptide repeats in ALS progression

“…This shows unequivocally that Nf-L and Nf-H proteins, to a different degree, outperform their Abs/ICs in the separation of ALS sub-groups from HC based on rate of disease progression in line with previously reported data 8,20,29 Mutations that diminish or eliminate C9orf72 function in mice cause a severe state of autoimmunity with loss of tolerance for many nervous system autoantigens 30 . The significant down-regulation of T-regulatory cells, a prominent feature in ALS individuals with fast disease progression, is also likely to contribute to a reduced immunotolerance 4,31 . It is tempting to speculate that the increased levels of Nf Abs and of NfL ICs in ALS-F and in C9+ve cases may be the result of altered immunotolerance and enhanced autoimmunity to brain antigens which become established throughout disease progression.…”

An update on human astrocytes and their role in development and disease

“…It is noteworthy that FTLD linked genes such as C9ORF72, TBK1, TARDBP, and GRN are highly expressed in cells belonging to the immune system. Therefore, it is likely that these cells play an important role in the development of the disease (McCauley & Baloh, 2019). In C9-FTD cases accumulation of RNA foci has been observed in both the cerebellum and hiPSC derived astroglia (Gendron et al, 2013;Sareen et al, 2013).…”