Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against Aβ toxicity via attenuating Aβ-induced endoplasmic reticulum stress
Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against Aβ toxicity via attenuating Aβ-induced endoplasmic reticulum stress
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DOI：
10.1186/s12974-019-1429-0
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发表时间：
2019-02-13
影响因子：
9.3
通讯作者：
Shen, Yuxian
中科院分区：
文献类型：
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作者：
Xu, Shengchun;Di, Zemin;Shen, Yuxian
背景：β-淀粉样肽（Aβ）在细胞外的积累是阿尔茨海默病（AD）的病理标志之一，并导致神经元损失。中脑星形胶质细胞源性神经营养因子（MANF）是一种内质网（ER）应激诱导性神经营养因子。包括我们在内的许多团体已经证明，MANF 可以挽救多种神经系统疾病（例如帕金森病和脑缺血）中的神经元损失。然而，MANF是否在AD中发挥其针对Aβ神经毒性的保护作用仍不清楚。方法：在本研究中，通过免疫荧光染色、qPCR和Western blot分析MANF在Aβ(1-42)处理的神经元细胞以及APP/PS1转基因小鼠大脑中的特征性表达。还研究了 A beta(1-42) 暴露后 MANF 过表达、MANF 敲低或重组人 MANF 蛋白 (rhMANF) 对神经元活力、细胞凋亡和 ER 应激相关蛋白表达的影响。 结果：结果显示 APP/PS1 转基因小鼠大脑中 MANF 以及 ER 应激标志物免疫球蛋白结合蛋白 (BiP) 和 C/EBP 同源蛋白 (CHOP) 的表达增加小鼠和 A beta(1-42) 处理的神经元细胞。 MANF 过表达或 rhMANF 治疗部分保护免受 A beta(1-42) 诱导的神经元细胞死亡，与裂解的 caspase-3 显着减少相关，而使用 siRNA 敲低 MANF 会加重 A beta(1-42) 细胞毒性，包括 caspase-3 激活。进一MANF 作为 AD 治疗候选药物的适用性。
Background: Extracellular accumulation of amyloid beta-peptide (A beta) is one of pathological hallmarks of Alzheimer's disease (AD) and contributes to the neuronal loss. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-inducible neurotrophic factor. Many groups, including ours, have proved that MANF rescues neuronal loss in several neurological disorders, such as Parkinson's disease and cerebral ischemia. However, whether MANF exerts its protective effect against A beta neurotoxicity in AD remains unknown.Methods: In the present study, the characteristic expressions of MANF in A beta(1-42)-treated neuronal cells as well as in the brains of APP/PS1 transgenic mice were analyzed by immunofluorescence staining, qPCR, and Western blot. The effects of MANF overexpression, MANF knockdown, or recombination human MANF protein (rhMANF) on neuron viability, apoptosis, and the expression of ER stress-related proteins following A beta(1-42) exposure were also investigated.Results: The results showed the increased expressions of MANF, as well as ER stress markers immunoglobulin-binding protein (BiP) and C/EBP homologous protein (CHOP), in the brains of the APP/PS1 transgenic mice and A beta(1-42)-treated neuronal cells. MANF overexpression or rhMANF treatment partially protected against A beta(1-42)-induced neuronal cell death, associated with marked decrease of cleaved caspase-3, whereas MANF knockdown with siRNA aggravated A beta(1-42) cytotoxicity including caspase-3 activation. Further study demonstrated that the expressions of BiP, ATF6, phosphorylated-IRE1, XBP1s, phosphorylated-eIF2 alpha, ATF4, and CHOP were significantly downregulated by MANF overexpression or rhMANF treatment in neuronal cells following A beta(1-42) exposure, whereas knockdown of MANF has the opposite effect.Conclusions: These findings demonstrate that MANF may exert neuroprotective effects against A beta-induced neurotoxicity through attenuating ER stress, suggesting that an applicability of MANF as a therapeutic candidate for AD.