Blood-CNS barrier dysfunction in amyotrophic lateral sclerosis: Proposed mechanisms and clinical implications

Abstract

There is strong evidence for blood-brain and blood-spinal cord barrier dysfunction at the early stages of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Since impairment of the blood-central nervous system barrier (BCNSB) occurs during the pre-symptomatic stages of ALS, the mechanisms underlying this pathology are likely also involved in the ALS disease process. In this review, we explore how drivers of ALS disease, particularly mitochondrial dysfunction, astrocyte pathology and neuroinflammation, may contribute to BCNSB impairment. Mitochondria are highly abundant in BCNSB tissue and mitochondrial dysfunction in ALS contributes to motor neuron death. Likewise, astrocytes adopt key physical, transport and metabolic functions at the barrier, many of which are impaired in ALS. Astrocytes also show raised expression of inflammatory markers in ALS and ablating ALS-causing transgenes in astrocytes slows disease progression. In addition, key drivers of neuroinflammation, including TAR DNA-binding protein 43 (TDP-43) pathology, matrix metalloproteinase activation and systemic inflammation, affect BCNSB integrity in ALS. Finally, we discuss the translational implications of BCNSB dysfunction in ALS, including the development of biomarkers for disease onset and progression, approaches aimed at restoring BCNSB integrity and in vitro modelling of the neurogliovascular system.

Network Spreading and Local Biological Vulnerability in Amyotrophic Lateral Sclerosis

“…This observation points to possible vascular dysfunction in ALS, potentially explaining the consistent enrichment of metabolic categories. The finding is consistent with previous reports that show a reduction in pericytes in the spinal cord in ALS [46,65], and interestingly, that these changes occur even prior to the initial clinical manifestations of the disease [128]. Collectively, these findings show that the spatial patterning of atrophy in ALS depends on both network structure as well as local molecular and cellular features that confer greater vulnerability to the disease.…”

Choroid plexus enlargement in amyotrophic lateral sclerosis patients and its correlation with clinical disability and blood-CSF barrier permeability

“…Due to its noninvasive and easy-to-implement nature, we suggest that early measurement of CP volume may be a potential approach for improving the diagnostic delay in ALS, for example, CP volume may be considered as a potential variable in a diagnostic model in the future [ 37 ]. Moreover, because the onset of ALS seems to involve a multistep process with a long preclinical stage and widespread BCSFB dysfunction that can be detected even in the presymptomatic-stage of ALS, we suggest that, similar to other neurodegenerative diseases, CP enlargement may also emerge in earlier stages in ALS patients [ 2 – 5 , 23 , 24 ]. Thus, future studies should be conducted to further examine whether CP enlargement can be detected in the earlier stages of ALS patients, for example, in ALS patients at King’s stage 1 or even in presymptomatic-stage patients with ALS, and the diagnostic performance of the CP volume in distinguishing between ALS and ALS-mimic diseases [ 1 , 5 , 34 , 38 ].…”

“…To date, similar to other neurodegenerative diseases, the drivers of CP abnormalities in ALS remain largely unclear [ 13 – 18 ]. Recently, Steinruecke et al proposed that mitochondrial dysfunction, astrocyte abnormalities and inflammation may contribute to BCNSB abnormalities in ALS [ 23 ]. As the CP is an important part of the BCNSB system, we suggest that these factors may also be involved in CP abnormalities in ALS [ 23 , 24 ].…”

“…Recently, Steinruecke et al proposed that mitochondrial dysfunction, astrocyte abnormalities and inflammation may contribute to BCNSB abnormalities in ALS [ 23 ]. As the CP is an important part of the BCNSB system, we suggest that these factors may also be involved in CP abnormalities in ALS [ 23 , 24 ]. In particular, in line with previous postmortem findings, we found that CP abnormalities can be detected in 12 genetic ALS patients, further supporting this hypothesis [ 21 , 36 – 40 ].…”

Cellular and Noncellular Approaches for Repairing the Damaged Blood–CNS–Barrier in Amyotrophic Lateral Sclerosis

“…Comprehensive reviews [ 16 , 17 ] have discussed not only the mechanisms underlying B-CNS-B impairment and translational implications of barrier dysfunction in ALS, but also potential strategies for restoring barrier integrity. Mirian et al [ 17 ] emphasized that B-CNS-B “structural and functional abnormalities are likely implicated in ALS pathophysiology and may occur upstream to neurodegeneration”.…”