Abstract
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease. HD patients present with movement disorders, behavioral and psychiatric symptoms and cognitive decline. This review summarizes the contribution of microglia and astrocytes to HD pathophysiology. Neuroinflammation in the HD brain is characterized by a reactive morphology in these glial cells. Microglia and astrocytes are critical in regulating neuronal activity and maintaining an optimal milieu for neuronal function. Previous studies provide evidence that activated microglia and reactive astrocytes contribute to HD pathology through transcriptional activation of pro-inflammatory genes to perpetuate a chronic inflammatory state. Reactive astrocytes also display functional changes in glutamate and ion homeostasis and energy metabolism. Astrocytic and microglial changes may further contribute to the neuronal death observed with the progression of HD. Importantly, the degree to which these neuroinflammatory changes are detrimental to neurons and contribute to the progression of HD pathology is not well understood. Furthermore, recent observations provide compelling evidence that activated microglia and astrocytes exert a variety of beneficial functions that are essential for limiting tissue damage and preserving neuronal function in the HD brain. Therefore, a better understanding of the neuroinflammatory environment in the brain in HD may lead to the development of targeted and innovative therapeutic opportunities.
Highlights
Neuroinflammation has been used to describe the infiltration of peripheral immune cells in the central nervous system (CNS), the term is currently used in relation to neurodegenerative diseases
The mitogen-activated protein kinase (MAPK) pathway is activated in many cell types in patients with neurodegenerative conditions and mouse models, but there is no evidence showing that it is directly involved in the initiation of astrocyte reactivity and activation of microglia (Bachstetter et al, 2011; Ben Haim et al, 2015a)
While a few studies suggest that reactive astrocytes might have beneficial effects and promote neuronal survival in neurodegenerative and other CNS disorders, there is a lack of Huntington’s disease (HD) focused research (Escartin and Bonvento, 2008; Hamby and Sofroniew, 2010)
Summary
Neuroinflammation has been used to describe the infiltration of peripheral immune cells in the central nervous system (CNS), the term is currently used in relation to neurodegenerative diseases. M1 microglia are suggested to have a more ‘‘classic’’ role in the inflammatory response and are thought to be the major initiators of both innate and adaptive immunity in the brain (Nakagawa and Chiba, 2014) These cells have a phagocytic function and will release cytotoxic factors such as nitric oxide (NO), reactive oxygen species (ROS) and quinolinic acid to confer toxicity to invading pathogens (Lull and Block, 2010; Benarroch, 2013; Nakagawa and Chiba, 2014). Microglia have been observed to adopt an increased inflammatory profile (Norden and Godbout, 2013) This is a phenomenon referred to as microglial priming and refers to the upregulation of proteins such as major histocompatibility complex class II (MHCII) molecules, integrins and toll-like receptors which are activated in an inflammatory response (Norden and Godbout, 2013). This may contribute to the chronic inflammation seen in several neurodegenerative diseases including AD, PD and HD
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