Fighting Neurodegeneration by Understanding Inflammation

Neurodegenerative diseases are one of the most pressing challenges of our time and teasing out the cellular mechanisms underpinning these diseases is a key goal for researchers in the field. We talked to Stéphane Martinez of CISBIO, a leading life sciences and diagnostics company, to discuss how researchers can access information on neurodegenerative mechanisms and how we are beginning to recognize the contribution of the immune system to neurodegeneration.

Ruairi Mackenzie (RM): Why is there such an urgent need to develop therapies for neurodegenerative disease?

Stéphane Martinez (SM): It is reported that about 50 million people suffer from a neurodegenerative disorder or dementia across the globe and the number of patients affected is expected to rise to over 150 million by 2050. Moreover, since the major risk factor of neurodegenerative diseases remains aging and given that the global population’s lifespan continues to increase with each generation, the future will see neurodegeneration place an increased burden on public health in many developed countries. Given the surging cost of these diseases for healthcare systems, there is an urgent need to invest in drug discovery research to further delineate the major neurodegeneration mechanisms and pave the way for the discovery of new and innovative therapies.

RM: What is the role of our brain’s immune system in the pathogenesis of these diseases?

SM: The lack of disease-modifying treatments for the most common neurodegenerative pathologies, such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and frontotemporal dementia, originates from the complexity of the pathophysiological mechanisms behind these diseases, such as a multifactorial etiology.

Proteostasis dysregulation, which refers to the breakdown of the normal balance of proteins within cells, is a common hallmark of all these disorders. The dysfunction stems from a defective proteasome and autophagy system, mitochondrial dysfunction and oxidative stress. However, there is emerging evidence demonstrating that the chronic inflammation and activation of the brain’s immune system is a crucial facilitator of these neurodegenerative processes.

Therefore, a great deal of research goes into improving our understanding of the regulation and response of glial cells in the early phases of disease progression.

Cisbio has produced a neurodegenerative diseases booklet where the reader will be able to find insights into the pathophysiology and molecular mechanisms of the most prominent progressive central nervous system diseases.

RM: How can understanding neuroinflammation help us develop therapies for neurodegenerative disease?

SM: Chronic neuroinflammation and the related innate immune response triggered by microglial and astrocyte cells play a major role in the development of neurodegenerative diseases. We have recently published a neuroscience guide that provides an overview on the current knowledge of the neuroinflammation pathways and details the contribution of glial cells to neurodegeneration.

In the absence of dysregulation, glial cells and the brain’s immune cells elicit protective mechanisms to locally and rapidly respond to defective neurons, injury, and to damaged cells or neuronal invasion. In a healthy context, the neuroinflammation is transient and maintains the homeostasis in the brain. However, a sustained inflammation and dysregulation of the microglial and astrocyte cells adversely impacts homeostasis in the brain and has been shown to exacerbate disease progression.

The aim of neuroscience research in this area is to acquire an in-depth understanding of the chronological events that lead to neuroinflammation in order to promote neuroprotective pathways and alleviate the harmful response.

RM: What are the hallmarks of neurodegenerative disease and what are the assays most commonly used to assess them?

SM: Neurodegenerative diseases have been correlated to proteinopathies, owing to the excessive accumulation of misfolded, hyperphosphorylated and aggregated proteins. These protein inclusions within neurons represent the primary hallmark of the major disorders such as Tau and amyloid-β proteins in Alzheimer’s disease, α-Synuclein in Parkinson’s disease, TDP-43 in the amyotrophic lateral sclerosis among others. Our company already provides a large selection of life science assays to quantify these valuable biomarkers that represent the key signature of neurodegenerative diseases.

Protein aggregation is increasingly considered a late stage hallmark of the disease. The key challenge is to identify biomarkers that are detected early, well before the symptom’s apparition. Our goal is to develop assays to track dysfunction in neuronal protein degradation mechanisms, such as autophagy and mitophagy, as well as important markers of neuroinflammation to tackle attractive targets and open new hopes for the identification of innovative treatments.

RM: How can we maximize the effectiveness of these assays to help researchers and ultimately patients?

SM: Our commitment to better serve scientists hinges on the development of highly reproducible, sensitive, high-throughput, and specific assays validated using the most physiologically relevant biological models. Our R&D efforts are focused on generating highly qualitative and quantitative data on primary cells, human induced pluripotent stem cell-derived astrocytes, human induced pluripotent stem cell-derived microglia and on brain extracts. All the educational material provided in addition to our innovative reagents are available on our website.

The brain is a very complex organ, defined by a sophisticated network of interactions between the different types of neurons and glial cells, which deserves our greatest attention. Our next stage is to consider working on physiologically relevant microtissues that will accurately mimic the interactions between brain cells and ultimately the native organ tissue.

Stéphane Martinez was speaking to Ruairi J Mackenzie, Science Writer for Technology Networks