Cortical Neurotoxic Astrocytes with Early ALS Pathology and miR-146a Deficit Replicate Gliosis Markers of Symptomatic SOD1G93A Mouse Model

被引:58
作者
Gomes, Catia [1 ]
Cunha, Carolina [1 ]
Nascimento, Filipe [2 ]
Ribeiro, Joaquim A. [2 ,3 ]
Vaz, Ana Rita [1 ,4 ]
Brites, Dora [1 ,4 ]
机构
[1] Univ Lisbon, Res Inst Med iMed ULisboa, Fac Pharm, Av Prof Gama Pinto, P-1649003 Lisbon, Portugal
[2] Univ Lisbon, Inst Mol Med, Unit Neurosci, Lisbon, Portugal
[3] Univ Lisbon, Inst Pharmacol & Neurosci, Fac Med, Lisbon, Portugal
[4] Univ Lisbon, Dept Biochem & Human Biol, Fac Pharm, Lisbon, Portugal
关键词
ALS astrocytes; Cerebral cortex; Inflammatory-associated microRNAs; Motor neurons; Pre-symptomatic and symptomatic stages; Transgenic hSOD1G93A mice; AMYOTROPHIC-LATERAL-SCLEROSIS; MOTOR-NEURON DEGENERATION; SUPEROXIDE-DISMUTASE; SPINAL-CORD; DISEASE PROGRESSION; REACTIVE ASTROCYTES; TNF-ALPHA; MICROGLIA; STRESS; EXPRESSION;
D O I
10.1007/s12035-018-1220-8
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron (MN) loss. Recent evidences highlight astrocytes as important players in MN death, but the mechanism-based neurotoxicity is still unknown. It is also unclear whether activation of astrocytes in ALS occurs differently in the cerebral cortex and spinal cord. We investigated glial and neuronal alterations in the cortex of SOD1G93A (mSOD1) mice in pre-symptomatic and symptomatic stages. We also characterized astrocytes isolated from the cortex of 7-day-old mSOD1 mice for their aberrancy and MN-induced degenerative effects. In the early stage, we identified a reduction of cell proliferation, NF-kB expression, and of vimentin and micro(miR)-146a expression, suggesting a restrained cortical inflammatory status. However, increased NF-kB expression, cell proliferation, and gene expression of HMGB1, connexin43andS100B were distinctive of the symptomatic stage, together with MN loss, downregulated unfold protein response, and decreased expression of synaptic proteins, together with that of miR-125b, miR-21, miR-146a, GFAP, and glutamate transporters. Astrocytes cultured for 13days in vitro showed comparable NF-kB expression and cell proliferation increase, as well as similar microRNA and gene/protein expression profiles (decreased miR-21, miR-146a, GLT-1 and GFAP, and upregulated HMGB1, S100B and connexin-43), thus sustaining astrocytes as the major contributors of cortical homeostasis deregulation in the symptomatic stage. These reactive astrocytes reduced neurite length and synaptophysin expression in NSC-34/hSOD1WT MN-like cells, and induced mitochondria dysfunction, PSD-95 downregulation, metalloproteinase-9 activation, and late apoptosis in NSC-34/hSOD1G93A cells. Data indicate that astrocytes in mSOD1 mice model acquire early phenotypic aberrancies and highlight downregulated miR-146a as a biomarker and drug target in ALS.
引用
收藏
页码:2137 / 2158
页数:22
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