In recent years, increasing attention has been given to the role of unresolved, chronic inflammation in the development of neurodegenerative disease. Normal tissue maintenance requires the involvement of immune cells, and inflammatory signaling is disruptive to that process. In the brain, immune cells take on a greater range of tasks than is the case elsewhere, becoming involved in maintenance of synaptic connections between neurons, for example. That too is disrupted by inflammatory signaling that changes the behavior of these cells.
Chronic inflammation in the absence of the usual causes, pathogens and injury, is a feature of aging. Researchers are investigating the causes of inflammation and mechanisms of regulation of inflammation in search of ways to damp down the inappropriate excessive inflammatory signaling of aging without also suppressing the necessary inflammation required for a robust immune defense. Some of the causes are reasonably well known. Senescent cells accumulate in tissues throughout the body, including the brain, and secrete pro-inflammatory signaling. DNA debris from cells damaged or destroyed by other processes of aging are misidentified by innate immune cells, that become inflammatory as a result of recognizing these damage-associated molecular patterns.
When it comes to inflammation in the brain, more research is focused on regulation than on causes, alas, but that is ever the case. Today's open access paper is an example of the type. Here, researchers review what is known of the role of galectins in the regulation of neuroinflammation. This is the sort of work that typically leads to screening programs that attempt to find small molecules that can adjust the behavior of one of the galectin interactions with minimal side-effects. Success depends as much on a correct understanding of the behavior and relevance of the target as it does on the quality of the small molecule interaction.
Advancements in medicine have increased the longevity of humans, resulting in a higher incidence of chronic diseases. Due to the rise in the elderly population, age-dependent neurodegenerative disorders are becoming increasingly prevalent. The available treatment options only provide symptomatic relief and do not cure the underlying cause of the disease. Therefore, it has become imperative to discover new markers and therapies to modulate the course of disease progression and develop better treatment options for the affected individuals. Growing evidence indicates that neuroinflammation is a common factor and one of the main inducers of neuronal damage and degeneration.
This review focuses on summarizing the immune-regulatory activities of three predominant members of the galectin (Gal) family - Gal-1, Gal-3, and Gal-9 - which are known to play a significant role in neurodegenerative ailments. Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) display similar characteristics, including native protein accumulation, neuronal degeneration, and cognitive and behavioral impairment.
Gal-1 mRNA and protein levels have been shown to be higher in the spinal cords of SOD1 mice displaying phenotypes similar to ALS in humans. In addition, higher mRNA and protein expression of Gal-3 and Gal-9 has been observed in the spinal cords of SOD1 mice and sporadic ALS patients. Gal-3 specifically has been identified as a biomarker in serum, plasma, and/or cerebrospinal fluid (CSF) in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). It has also shown detrimental regulation of inflammatory responses in AD. Further, moderate cognitive impairment in AD has been associated with Gal-9.
This information suggests that targeting Gals has a promising therapeutic potential to treat inflammatory and neurodegenerative disorders. In this review, we discuss the role of Gals in the causation and progression of neurodegenerative disorders. We describe the role of Gals in microglia and astrocyte modulation, along with their pro- and anti-inflammatory functions. In addition, we discuss the potential use of Gals as a novel therapeutic target for neuroinflammation and restoring tissue damage in neurodegenerative diseases.