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  • Excessive neuroinflammation is one of

    2019-07-30

    Excessive neuroinflammation is one of the pathogenic hallmarks of neurodegenerative diseases and is thought to contribute both to the initiation and progression of neurodegeneration (Reviewed by ; and ). Therefore, understanding the regulatory mechanisms involved in components of the inflammatory response has been an intense area of study. Although the vast majority of research to date has focused on microglia as key regulators of neuroinflammation in neurodegeneration, existing and emerging data highlight the importance and contribution of astrocytes to the inflammation found in neurodegenerative diseases , , , . Astrocyte reactivity is a sensitive and robust response to many different types of pathology and is regulated by a wide array of processes, including epigenetic regulation. Growing evidence indicates that astrocytes are important in protection of neurons, while at the same time, they can also contribute to neuroinflammation and neurodegeneration when converted to a reactive state. However, many of the mechanisms surrounding astrocyte-induced neuroprotection or neurotoxicity are still not well-established. Therefore, greater understanding of these factors, including epigenetic alterations that regulate astrocyte functions, could better elucidate the precise role of astrocytes in neurodegenerative diseases and provide a pathway to target astrocytes for neuroprotection. Astrocytes are the largest population of glial cells in the CNS and were traditionally viewed as only structural elements supporting Tunicamycin structure (Hence their name, meaning “glue” in Greek .). However, it is now obvious that astrocytes have many other important functions in the CNS. Proper astrocyte function is essential for normal development, including developmental synapse formation and pruning through both secreted factors and direct contact with the synapse , . In adults, evidence indicates that hippocampal astrocytes have an important role in Tunicamycin promoting neurogenesis from adult neural stem cells . Similarly, astrocytes exhibit extensive processes that contact neural elements, especially synapses and nodes of Ranvier, and astrocyte end feet cover nearly all of the brain microvasculature. These contacts position astrocytes as the main conduit for neuron-glia interactions . Astrocytes, far from being merely physical support cells, actively modulate synaptic glutamate levels, scavenge free radicals, produce neurotrophic factors, and regulate the blood brain barrier , , . The importance of astrocytes for neuronal survival was confirmed by the study that found conditional ablation of astrocytes in adult mice led to significant neurodegeneration . Additionally, multiple reports have demonstrated that reactive astrocytes may exacerbate inflammatory processes that can lead to neurodegeneration , . Indeed, astrocytes exposed to an inflammatory stimulus also produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and TNF-α, along with increased production of reactive oxygen species (ROS) . This response is known as reactive astrogliosis, and is the mechanism by which astrocytes respond to injuries such as trauma, infection, misfolded protein accumulation, and excitotoxicity in neurodegenerative disease such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) (reviewed in ). The cell-to-cell communication of astrocytes, neurons, and microglia in neurodegenerative diseases is detailed in , with the factors involved in spreading these damaging factors between cell types. Reactive astrogliosis is an evolutionary conserved response that is a constitutive, graded, and multi-staged process . This reactive state is characterized by both molecular and morphological changes. These include increased expression of the glial fibrillary acidic protein (GFAP), vimentin, and nestin, accompanying a reduction in the number of primary branches and hypertrophy of the cell body and remaining processes . Recently, Liddelow et al. demonstrated that pro-inflammatory microglia can induce conversion into reactive astrocytes, and that these reactive astrocytes are cytotoxic to neurons . Complicating the issue however, Rappold and Tieu reported that astrocytes did not respond in a uniform manner, and instead represented a heterogeneous population , some of which are protective. Therefore, there is a need to elucidate the mechanisms surrounding astrocyte responses to different neurologic conditions and the various neurodegenerative diseases. A comparison of astrocyte gene expression in either a model of ischemia or an endotoxin inflammatory model demonstrated that at least 50% of the injury-altered gene expression was disease specific . These points underscore the fact that astrocytes are a complex CNS cell-type that exhibits a differential, heterogeneous response depending on context. Thus, understanding the mechanisms leading to regulation and differential responses may provide insight into the pathogenic process of neurodegeneration and identify novel targets for intervention.