Elusive roles for reactive astrocytes in neurodegenerative diseases

Abstract

Astrocytes play crucial roles in the brain and are involved in the neuroinflammatory response. They become reactive in response to virtually all pathological situations in the brain such as axotomy, ischemia, infection, and neurodegenerative diseases (ND). Astrocyte reactivity was originally characterized by morphological changes (hypertrophy, remodeling of processes) and the overexpression of the intermediate filament glial fibrillary acidic protein (GFAP). However, it is unclear how the normal supportive functions of astrocytes are altered by their reactive state. In ND, in which neuronal dysfunction and astrocyte reactivity take place over several years or decades, the issue is even more complex and highly debated, with several conflicting reports published recently. In this review, we discuss studies addressing the contribution of reactive astrocytes to ND. We describe the molecular triggers leading to astrocyte reactivity during ND, examine how some key astrocyte functions may be enhanced or altered during the disease process, and discuss how astrocyte reactivity may globally affect ND progression. Finally we will consider the anticipated developments in this important field. With this review, we aim to show that the detailed study of reactive astrocytes may open new perspectives for ND.

Natural product HTP screening for attenuation of cytokine-induced neutrophil chemo attractants (CINCs) and NO2− in LPS/IFNγ activated glioma cells

“…Outward manifestation of reactive gliosis/neuro inflammatory processes are associated with head trauma (Lopez-Rodriguez, Acaz-Fonseca, 2015), ischemia (Li, Xu, 2015c) infection (Ben Haim, Carrillo-de Sauvage, 2015a) and neuronal lesions infiltrated with protein aggregates such as amyloid β (Aβ), neurofibrillary tangles (Ben Haim, Carrillo-de Sauvage, 2015a) α-synucleinA53T (Ben Haim, Carrillo-de Sauvage, 2015a, Yang, Wang, 2015) which are common to AD and PD pathologies, respectively. Sustained neuro-inflammatory processes can be perpetuated by dying cells which release DAMPs such as high mobility group box-1 (HMGB1)/capable of activating innate immunity to remove necrotic debris, then worsening the neurodegenerative process (Frank, Adhikary, 2016, Kigerl, de Rivero Vaccari, 2014).…”

“…These are known to include specific targets such as janus kinase/signal transducer and activator of transcription (JAK/STAT) (Ben Haim, Carrillo-de Sauvage, 2015a, Ben Haim et al, 2015b, Wang et al, 2015b), nuclear Factor of Kappa light polypeptide gene enhancer in B-cells (NF-κB), calcineurin, Mitogen-Activated Protein Kinases (MAPKs) (Ben Haim, Carrillo-de Sauvage, 2015a) or Notch1-STAT3-ETB (LeComte et al, 2015). These are the indirect controls account for biological events such as induction of iNOS, release of NO, MCP-1 and CINCS.…”

“…Inflammatory processes occurring within CNS (by glial cells) contribute vulnerability by initiating vascular damage (Doyle et al, 2015, Weaver et al, 2010) neurological insult (Bodnar et al, 2015, Garcia et al, 2016) and destruction to the blood brain barrier (BBB). (Adelson et al, 1998) While CNS glial cells exert an influential role in neurodevelopment, neuronal homeostasis and CNS detoxification, on the flip side, detrimental inflammatory processes can arise from head trauma (Lopez-Rodriguez et al, 2015), ischemia (Li et al, 2015c) infection (Ben Haim et al, 2015a) lysosomal storage diseases (Rama Rao and Kielian, 2015) and protein aggregates of amyloid β (Aβ) (Ben Haim, Carrillo-de Sauvage, 2015a) and α-synuclein A53T (Ben Haim, Carrillo-de Sauvage, 2015a, Yang et al, 2015) common to AD and PD, respectively. Once neurodegeneration ensues, reactive gliosis (Mohn and Koob, 2015) circumscribing degenerative neurons can occur due to debris generated as danger-associated molecular patterns (DAMPs), (Frank et al, 2016, Kigerl et al, 2014) leading to a cyclic perpetuated release of pro-inflammatory neurotoxic cytokines (Hammond et al, 2015, Mohn and Koob, 2015).…”

Glial and neuroinflammatory targets for treating substance use disorders

“…Thus, some studies have shown abstinence-induced decreases in cortical astrocytes, increases in nucleus accumbens astrocytes, and others show no change in astrocytes (Bull et al, 2014; Miguel-Hidalgo, 2006; Miguel-Hidalgo et al, 2002). The ramifications of density changes in astrocytes, as measured by GFAP expression, is not yet fully understood, but may reflect the engagement of astrocytes in inflammatory signaling (see above) or represent changes in astrocyte functioning at the perisynaptic sites (Ben Haim et al, 2015). …”

Análise dos efeitos clínico-radiológicos, histopatológicos e bioquímicos da derivação ventrículo-subcutânea na hidrocefalia induzida por caulim em ratos

“…Desempenham funções importantes, tais como a sustentação e a nutrição dos neurônios, além de serem reguladores das funções neuronais (BEN HAIM et al, 2015).…”