Abstract
Cerebellar ataxias (CAs) consist of a heterogeneous group of neurodegenerative diseases hallmarked by motor deficits and deterioration of the cerebellum and its associated circuitries. Neuroinflammatory responses are present in CA brain, but how neuroinflammation may contribute to CA pathogenesis remain unresolved. Here, we investigate whether transforming growth factor (TGF)-β1, which possesses anti-inflammatory and neuroprotective properties, can ameliorate the microglia-mediated neuroinflammation and thereby alleviate neurodegeneration in CA. In the current study, we administered TGF-β1 via the intracerebroventricle (ICV) in CA model rats, by intraperitoneal injection of 3-acetylpyridine (3-AP), to reveal the neuroprotective role of TGF-β1. The TGF-β1 administration after 3-AP injection ameliorated motor impairments and reduced the calbindin-positive neuron loss and apoptosis in the brain stem and cerebellum. Meanwhile, 3-AP induced microglial activation and inflammatory responses in vivo, which were determined by morphological alteration and an increase in expression of CD11b, enhancement of percentage of CD40 + and CD86 + microglial cells, upregulation of pro-inflammatory mediators, tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and a downregulation of neurotrophic factor, insulin-like growth factor (IGF)-1 in the brain stem and cerebellum. TGF-β1 treatment significantly prevented all the changes caused by 3-AP. In addition, in vitro experiments, TGF-β1 directly attenuated 3-AP-induced microglial activation and inflammatory responses in primary cultures. Purkinje cell exposure to supernatants of primary microglia that had been treated with TGF-β1 reduced neuronal loss and apoptosis induced by 3-AP-treated microglial supernatants. Furthermore, the protective effect was similar to those treated with TNF-α-neutralizing antibody. These findings suggest that TGF-β1 protects against neurodegeneration in 3-AP-induced CA rats via inhibiting microglial activation and at least partly TNF-α release.
Highlights
Cerebellar ataxias (CAs) comprise a heterogeneous group of neurodegenerative diseases hallmarked by dysfunction of the cerebellum along with a host of neurological symptoms (Brusse et al, 2007; Marmolino and Manto, 2010)
Cerebellar ataxia is considered to be a range of brain disorders characterized by lack of motor coordination induced by disturbances in the cerebellum and its associated circuits (Marmolino and Manto, 2010). 3-AP, known as methyl β-pyridyl ketone, is a metabolic antagonist utilized to decrease nicotinamide level of laboratory animals in research
A large number of laboratory animals with neurological mutations have been reported and numerous relevant animal models mimicking the phenotype of CAs are becoming available (Manto and Marmolino, 2009), the administration of 3-AP has still been suggested as a classic method to induce the CA animal model and provokes many characteristics similar to the typical features of CA in human (Janahmadi et al, 2009; Wecker et al, 2017)
Summary
Cerebellar ataxias (CAs) comprise a heterogeneous group of neurodegenerative diseases hallmarked by dysfunction of the cerebellum along with a host of neurological symptoms (Brusse et al, 2007; Marmolino and Manto, 2010). In a mouse model of SCA1, astrocytes and microglia are activated very early in disease pathogenesis even in the absence of neuronal death and glial activation closely correlates with SCA1 progression with the development of glia-based biomarkers to follow disease progression (Cvetanovic et al, 2015). The results from proton magnetic resonance spectroscopy research indicate that gliosis is closely related to disease severity in SCA1 patients (Oz et al, 2010). These findings demonstrate that glia-mediated neuroinflammation actively contributes to the pathogenesis of CA
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
