Cellular Models of Reactive Astrocytes ─ New Insights into Prion Diseases and Other Neurodegenerative Disorders

Prion disease, also Creutzfeldt-Jakob Disease (CJD), is a group of rare neurodegenerative disorders triggered by abnormal folding of the cellular prion protein (PrPC) into the aggregation prone for PrPSc, accompanied by neuronal death, spongiform degeneration, and gliosis in the central nervous system (CNS).

After decades of research, questions such as, what induces neuro-degeneration and what is the role of non-neuronal cells in this process, yet remain unrevealing. There are studies suggesting a critical involvement of astrocytes, the reactive states of which are often reported in pathogenesis of prion diseases, thus reactive astrocytes might become a new target related to reactive astrocytes, which sheds some light on the development of relevant therapeutic strategies.

Astrocytes are an essential component of the CNS which represent the most abundant glial cell type in human brain. Being closely associated with neuronal synapses, astrocytes are responsible for regulating the transmission of electrical impulses within the brain, providing nutrients for neurons, as well as keeping extracellular ion balance, and play a key role in the repair process of brain and spinal cord after traumatic injuries. Under chronic neurodegeneration associated with prion diseases, astrocytes undergo significant transcriptional, morphological and functional transformation resulting in reactive phenotypes, but it is not clear whether polarization into reactive state produces the neurotoxic or neuroprotective outcome.

It is difficult to study the mechanisms of neural functioning due to the inherent complexity of neural tissue, and experiments using animal models of prion infection on the other side are time-consuming and hardly can be used for screening approaches, so cell models become the ideal choice to study the mechanisms of prion infection and pathogenesis as well as for screening compounds with therapeutic potential.

Establishing sub-population specific cellular models of reactive astrocytes can help to explore the contribution of sub-populations of reactive astrocytes, their differential regulation of signaling cascades, and the interaction with neurons and microglia during prion pathogenesis. CO2-independent nutrient medium can enable neurons to be in ambient CO2 levels so that live neuron cell assays can be allowed. Single cell-based transcriptomics and proteomics studies in these models could generate new meaningful findings and open the door for novel therapeutic strategies targeting astrocytes. Modulation of neurotoxic functions or augmentation of neuroprotective functions of reactive astrocytes could thus be achieved by application of small molecules or genetic manipulations.

More importantly, reactive astrocytes and astrocytosis are common characteristics of a wide variety of neurodegenerative disorders, not only prion diseases. It is therefore likely that studying the role of astrocytes in prion diseases will also unveil important insights into the role of astrocytes and astrocytosis in other neurodegenerative disorders.