The Diverse Roles of Reactive Astrocytes in the Pathogenesis of Amyotrophic Lateral Sclerosis

Yang, Kangqin; Liu, Yang; Zhang, Min

doi:10.3390/brainsci14020158

Cited by 6 publications

(2 citation statements)

References 157 publications

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“…Recently, immune dysregulation has been suspected [ 171 , 172 , 173 ], with neuroinflammation being invoked in general [ 174 , 175 , 176 ] and for ALS in particular [ 177 , 178 , 179 ], especially concerning activation of microglia and astrocytes [ 180 , 181 ]. It is interesting that microglia communicate with [ 182 ], and can be activated by [ 183 ], mast cells, unique effector immune cells that are ubiquitous in the body and are critical in allergies [ 184 ], but also inflammatory processes [ 185 ].…”

Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Cohen,

Mathew,

Dourvetakis

et al. 2024

Cells

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Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood–brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.

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Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Cohen,

Mathew,

Dourvetakis

et al. 2024

Cells

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“…Vascular alterations occur before symptom onset, leading to increased hypoxia that stresses cellular metabolism ( Nomura et al, 2019 ; Månberg et al, 2021 ). The combination of increased inflammation driven by microglia and release of toxic factors from astrocytes further stresses motor neurons, which includes elements of the complement system, pro-inflammatory cytokines such as tissue necrosis factor (TNF) as well as a reduced capacity of astrocytes to buffer extracellular glutamate that leads to neuronal glutamate excitotoxicity ( Clarke and Patani, 2020 ; Yang et al, 2024 ). With regards to which toxic factors are specifically released by astrocytes, it is not fully known but may contain a cocktail of the aforementioned factors with other novel, yet to be identified mediators ( Nagai et al, 2007 ).…”

Section: Als Pathophysiologymentioning

confidence: 99%

Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

Min,

Sarlus,

Harris

2024

Front. Mol. Neurosci.

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The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.

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Structural and molecular characterization of astrocyte and vasculature connectivity in the mouse hippocampus and cortex

Lorin,

Guiet,

Chiaruttini

et al. 2024

Glia

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The relation of astrocytic endfeet to the vasculature plays a key functional role in the neuro‐glia‐vasculature unit. We characterize the spatial organization of astrocytes and the structural aspects that facilitate their involvement in molecular exchanges. Using double transgenic mice, we performed co‐immunostaining, confocal microscopy, and three‐dimensional digital segmentation to investigate the biophysical and molecular organization of astrocytes and their intricate endfoot network at the micrometer level in the isocortex and hippocampus. The results showed that hippocampal astrocytes had smaller territories, reduced endfoot dimensions, and fewer contacts with blood vessels compared with those in the isocortex. Additionally, we found that both connexins 43 and 30 have a higher density in the endfoot and the former is overexpressed relative to the latter. However, due to the limitations of the method, further studies are needed to determine the exact localization on the endfoot. The quantitative information obtained in this study will be useful for modeling the interactions of astrocytes with the vasculature.

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The Diverse Roles of Reactive Astrocytes in the Pathogenesis of Amyotrophic Lateral Sclerosis

Cited by 6 publications

References 157 publications

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

Structural and molecular characterization of astrocyte and vasculature connectivity in the mouse hippocampus and cortex

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