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astrocytes and neurodegenerative disease

Cara L Croft, Pedro E Cruz, Daniel H Ryu, Carolina Ceballos-Diaz, Kevin H Strang, Brittany M Woody, Wen-Lang Lin, Michael Deture, Edgardo Rodríguez-Lebrón, Dennis W Dickson, Paramita Chakrabarty, Yona Levites, Benoit I Giasson, Todd E Golde
It has been challenging to produce ex vivo models of the inclusion pathologies that are hallmark pathologies of many neurodegenerative diseases. Using three-dimensional mouse brain slice cultures (BSCs), we have developed a paradigm that rapidly and robustly recapitulates mature neurofibrillary inclusion and Lewy body formation found in Alzheimer's and Parkinson's disease, respectively. This was achieved by transducing the BSCs with recombinant adeno-associated viruses (rAAVs) that express α-synuclein or variants of tau...
February 15, 2019: Journal of Experimental Medicine
Francisco Javier Carreras
Glaucoma has been recently characterized as a member of the group of anoikis-related diseases. Anoikis, a form of apoptosis, can be triggered by the unfastening of adherent junctions present in astrocytes. In those areas of the central nervous system in which the soma of the neurons or their axons and dendrites are metabolically dependent on the activity of astrocytes, a derangement of the lactate shuttle caused by a separation between the plasma membranes of neurons and astrocytes would result in metabolic impairment of the neurons themselves...
June 2019: Neural Regeneration Research
Clévio Nobrega, José M Codesso, Liliana Mendonça, Luis Pereira de Almeida
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly-inherited neurodegenerative disorder caused by the over-repetition of a CAG codon in the MJD1 gene. This expansion translates into a long polyglutamine tract that confers a toxic gain-of-function to the mutant protein - ataxin-3, leading to neurodegeneration in specific brain regions. No treatment able to modify the disease progression is available. However, we and others have previously shown that specific silencing mutant ataxin-3 by RNA interference with viral vectors is a promising therapeutic strategy for MJD...
February 14, 2019: Human Gene Therapy
MuhChyi Chai, Jun Kohyama
Non-cell-autonomous effects on neuronal cells are considered to be involved in the pathogenesis of neurodegenerative diseases but have yet to be mechanistically proven. In this issue of Stem Cell Reports, di Domenico et al. provide direct evidence that α-synuclein transferred from astrocytes exerts non-cell-autonomous neuronal dysfunction on dopaminergic neurons in Parkinson's disease (PD).
February 12, 2019: Stem Cell Reports
Jin-Sun Park, Yea-Hyun Leem, Jung-Eun Park, Do-Yeon Kim, Hee-Sun Kim
Parkinson's disease is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta. In the present study, we investigated whether β-Lapachone (β-LAP), a natural naphthoquinone compound isolated from the lapacho tree ( Tabebuia avellanedae ), elicits neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. β-LAP reduced the tyrosine hydroxylase (TH)-immunoreactive fiber loss induced by MPTP in the dorsolateral striatum, and alleviated motor dysfunction as determined by the rotarod test...
February 8, 2019: Biomolecules & Therapeutics
Alice Kunzler, Camila Tiefensee Ribeiro, Juciano Gasparotto, Lyvia Lintzmaier Petiz, Helen Thais da Rosa Silva, Jeferson Delgado da Silva, Rafael Bortolin, Priscila Oliveira de Souza, Fabiano Barreto, Pedro Espitia-Perez, Carlos Eduardo Schnorr, Nauana Somensi, José Cláudio Fonseca Moreira, Daniel Pens Gelain
Vitamin A (retinol) is involved in signaling pathways regulating gene expression and was postulated to be a major antioxidant and anti-inflammatory compound of the diet. Parkinson's disease (PD) is a progressive neurodegenerative disorder, characterized by loss of nigral dopaminergic neurons, involving oxidative stress and pro-inflammatory activation. The aim of the present study was to evaluate the neuroprotective effects of retinol oral supplementation against 6-hydroxydopamine (6-OHDA, 12 μg per rat) nigrostriatal dopaminergic denervation in Wistar rats...
February 7, 2019: Neurochemistry International
Maryam Kamarehei, Sussan Kabudanian Ardestani, Masoumeh Firouzi, Hamid Zahednasab, Mohammad Hossein Harirchian
The role of endoplasmic reticulum (ER) stress has been proposed in several neurodegenerative and autoimmune diseases and may contribute to neural apoptosis. The complex role of ER stress-mediated apoptosis introduces a novel angle on multiple sclerosis (MS) research. Nevertheless, the mechanisms through which ER stress intermediates apoptosis are not entirely understood. To this aim, we examined the expression of C/EBP homologous protein (CHOP), caspase-12, and protein disulfide isomerase (PDI) in mice with experimental autoimmune encephalomyelitis (EAE)...
February 6, 2019: Brain Research Bulletin
Khaled H Elfakhri, Ihab M Abdallah, Andrew D Brannen, Amal Kaddoumi
Alzheimer's disease (AD) is a complex neurodegenerative disorder with multiple dysfunctional pathways. Therefore, a sophisticated treatment strategy that simultaneously targets multiple brain cell types and disease pathways could be advantageous for effective intervention. To elucidate an effective treatment, we developed an in vitro high-throughput screening (HTS) assay to evaluate candidate drugs for their ability to enhance the integrity of the blood-brain barrier (BBB) and improve clearance of amyloid-β (Aβ) using a cell-based BBB model...
January 30, 2019: Neurobiology of Disease
Inma Castilla-Cortázar, Ignacio Iturrieta, Mariano García-Magariño, Juan E Puche, Irene Martín-Estal, Gabriel A Aguirre, Giovana Femat-Roldan, Leonel Cantu-Martinez, Úrsula Muñoz
Neurotrophic factors (NTFs) are a relevant group of secreted proteins that modulate growth, differentiation, repair, and survival of neurons; playing a role in the maintenance of the synaptic unions, dendrites and axons; also, being crucial for peripheral nervous system development and regulating plasticity in the adult central nervous system. On the other hand, insulin-like growth factor 1 (IGF-1) has been ascertained multiple beneficial actions in the brain: neuro-development, -protection, -genesis and plasticity...
January 29, 2019: Neuroscience
Liu Xiaoying, Tian Li, Shang Yu, Jiang Jiusheng, Zhang Jilin, Wei Jiayi, Liu Dongxin, Fang Wengang, Zhao Xinyue, Yu Hao, Chen Yuhua, Shang Deshu
Neuroinflammation is an important part of the development of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's and amyotrophic lateral sclerosis. Inflammatory factors destroy the balance of the microenvironment, which results in changes in neural stem cell differentiation and proliferation behaviour. However, the mechanism underlying inflammatory factor-induced NSC behavioural changes is not clear. Resistin is a proinflammatory and adipogenic factor and is involved in several human pathology processes...
January 28, 2019: Neurochemical Research
Yan-Qiu Cui, Yan Zheng, Gui-Lian Tan, Dong-Mei Zhang, Jun-Ya Wang, Xiao-Min Wang
Many studies have shown that (5R)-5-hydroxytriptolide is the optimal modified analogue of triptolide, possessing comparable immunosuppressive activity but much lower cytotoxicity than triptolide. Whether (5R)-5-hydroxytriptolide has preventive effects on neuroinflammation is unclear. This study was designed to pretreat primary astrocytes from the brains of neonatal Sprague-Dawley rats with 20, 100 and 500 nM (5R)-5-hydroxytriptolide for 1 hour before establishing an in vitro neuroinflammation model with 1.0 μg/mL lipopolysaccharide for 24 hours...
May 2019: Neural Regeneration Research
Md Jakaria, Md Ezazul Haque, Duk-Yeon Cho, Shofiul Azam, In-Su Kim, Dong-Kug Choi
NR4A2 is a nuclear receptor and a transcription factor, with distinctive physiological features. In the cell nuclei of the central nervous system, it is widely expressed and identified as a crucial regulator of dopaminergic (DA) neuronal differentiation, survival, and maintenance. Importantly, it has regulated different genes crucial for dopaminergic signals, and its expression has been diminished in both aged and PD post-mortem brains and reduced in PD patients. In microglia and astrocytes, the expression of NR4A2 has been found where it can be capable of inhibiting the expression of proinflammatory mediators; hence, it protected inflammation-mediated DA neuronal death...
January 25, 2019: Molecular Neurobiology
Xue Xue, Weiwei Zhang, Jifeng Zhu, Xiaojun Chen, Sha Zhou, Zhipeng Xu, Gang Hu, Chuan Su
Aquaporin-4 (AQP4), the main water-selective membrane transport protein in the brain, is localized to the astrocyte plasma membrane. Following the establishment of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) model, AQP4-deficient (AQP4-/- ) mice displayed significantly stronger microglial inflammatory responses and remarkably greater losses of tyrosine hydroxylase (TH+ )-positive neurons than did wild-type AQP4 (AQP4+/+ ) controls. Microglia are the most important immune cells that mediate immune inflammation in PD...
January 25, 2019: Journal of Cellular and Molecular Medicine
Arshed Nazmi, Robert H Field, Eadaoin W Griffin, Orla Haugh, Edel Hennessy, Donal Cox, Renata Reis, Lucas Tortorelli, Carol L Murray, Ana Belen Lopez-Rodriguez, Lei Jin, Ed C Lavelle, Aisling Dunne, Colm Cunningham
Type I interferons (IFN-I) are the principal antiviral molecules of the innate immune system and can be made by most cell types, including central nervous system cells. IFN-I has been implicated in neuroinflammation during neurodegeneration, but its mechanism of induction and its consequences remain unclear. In the current study, we assessed expression of IFN-I in murine prion disease (ME7) and examined the contribution of the IFN-I receptor IFNAR1 to disease progression. The data indicate a robust IFNβ response, specifically in microglia, with evidence of IFN-dependent genes in both microglia and astrocytes...
January 25, 2019: Glia
Ariful Islam, Yoshiteru Kagawa, Hirofumi Miyazaki, Subrata Kumar Shil, Banlanjo A Umaru, Yuki Yasumoto, Yui Yamamoto, Yuji Owada
Fatty acid-binding proteins (FABPs) bind and internalize long-chain fatty acids, controlling lipid dynamics. Recent studies have proposed the involvement of FABPs, particularly FABP7, in lipid droplet (LD) formation in glioma, but the physiological significance of LDs is poorly understood. In this study, we sought to examine the role of FABP7 in primary mouse astrocytes, focusing on its protective effect against reactive oxygen species (ROS) stress. In FABP7 knockout (KO) astrocytes, ROS induction significantly decreased LD accumulation, elevated ROS toxicity, and impaired thioredoxin (TRX) but not peroxiredoxin 1 (PRX1) signalling compared to ROS induction in wild-type astrocytes...
January 24, 2019: Molecular Neurobiology
Shen-Zhao Lu, Yong-Shun Guo, Pei-Zhou Liang, Shu-Zhen Zhang, Shu Yin, Yan-Qing Yin, Xiao-Min Wang, Fei Ding, Xiao-Song Gu, Jia-Wei Zhou
Background: Parkinson's disease (PD) is characterized by a chronic loss of dopaminergic neurons and the presence of proteinaceous inclusions (Lewy bodies) within some remaining neurons in the substantia nigra. Recently, astroglial inclusion body has also been found in some neurodegenerative diseases including PD. However, the underlying molecular mechanisms of how astroglial protein aggregation forms remain largely unknown. Here, we investigated the contribution of αB-crystallin (CRYAB), a small heat shock protein, in α-synuclein inclusion formation in astrocytes...
2019: Translational Neurodegeneration
Gouri Yogalingam, Amanda R Luu, Heather Prill, Melanie J Lo, Bryan Yip, John Holtzinger, Terri Christianson, Mika Aoyagi-Scharber, Roger Lawrence, Brett E Crawford, Jonathan H LeBowitz
Sanfilippo syndrome type B (Sanfilippo B; Mucopolysaccharidosis type IIIB) occurs due to genetic deficiency of lysosomal alpha-N-acetylglucosaminidase (NAGLU) and subsequent lysosomal accumulation of heparan sulfate (HS), which coincides with devastating neurodegenerative disease. Because NAGLU expressed in Chinese hamster ovary cells is not mannose-6-phosphorylated, we developed an insulin-like growth factor 2 (IGF2)-tagged NAGLU molecule (BMN 250; tralesinidase alfa) that binds avidly to the IGF2 / cation-independent mannose 6-phosphate receptor (CI-MPR) for glycosylation independent lysosomal targeting...
2019: PloS One
Yke Jildouw Arnoldussen, Torunn Kringlen Ervik, Mina Baarnes Eriksen, Ida Kero, Vidar Skaug, Shanbeh Zienolddiny
Despite the rigorous emission control measures in the ferroalloy industry, there are still emissions of dust during the production of various alloys. Dust particles were collected from laboratory scale processes where oxide particulate matter was formed from liquid silicon (metallurgical grade). The dust was produced in a dry air atmosphere to mimic industrial conditions. To investigate possible effects of ultrafine dust on the central nervous system, a human astrocytic cell line was employed to investigate inflammatory effects of particles as astrocytes play a number of active and neuron supporting roles in the brain...
January 16, 2019: International Journal of Molecular Sciences
James A Carroll, Bruce Chesebro
Prion disorders are transmissible diseases caused by a proteinaceous infectious agent that can infect the lymphatic and nervous systems. The clinical features of prion diseases can vary, but common hallmarks in the central nervous system (CNS) are deposition of abnormally folded protease-resistant prion protein (PrPres or PrPSc), astrogliosis, microgliosis, and neurodegeneration. Numerous proinflammatory effectors expressed by astrocytes and microglia are increased in the brain during prion infection, with many of them potentially damaging to neurons when chronically upregulated...
January 15, 2019: Viruses
Karol Kowalski, Agata Mulak
Disturbances along the brain-gut-microbiota axis may significantly contribute to the pathogenesis of neurodegenerative disorders. Alzheimer's disease (AD) is the most frequent cause of dementia characterized by a progressive decline in cognitive function associated with the formation of amyloid beta (Aβ) plaques and neurofibrillary tangles. Alterations in the gut microbiota composition induce increased permeability of the gut barrier and immune activation leading to systemic inflammation, which in turn may impair the blood-brain barrier and promote neuroinflammation, neural injury, and ultimately neurodegeneration...
January 31, 2019: Journal of Neurogastroenterology and Motility
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