Proteinase-activated receptor-2 exerts protective and pathogenic cell type-specific effects in Alzheimer's disease
Proteinase-activated receptor-2 exerts protective and pathogenic cell type-specific effects in Alzheimer's disease
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DOI：
10.4049/jimmunol.179.8.5493
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发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
Power, Christopher
中科院分区：
文献类型：
--
作者：
Afkhami-Goli, Amir;Noorbakhsh, Farshid;Power, Christopher
蛋白酶激活受体(PARs)是一个新的G蛋白偶联受体家族，其在神经退行性疾病中的作用尚不清楚。阿尔茨海默病(AD)是一种神经退行性疾病，定义为蛋白质错误折叠积累，同时伴有神经炎症和神经元死亡。我们报道了阿尔茨海默病患者脑神经元中蛋白水解酶激活受体2(PAR2)的表达受到抑制，而近端神经胶质细胞中PAR2的表达增加，同时促炎细胞因子和趋化因子的上调以及IL-4的表达降低(p<；0.05)。胶质细胞PAR2激活增加了甲酰肽受体-2(P<；0.01)的表达，这是一种纤维状42-AA形式的β-淀粉样蛋白(Aβ(1-42))的同源受体，增强了小胶质细胞介导的促炎反应，并抑制了星形胶质细胞IL-4的表达，导致神经元死亡(p<；0.05)。相反，神经元PAR2的激活保护人类神经元免受Aβ(1-42)的毒性影响(p<；0.05)，Aβ(1-42)是AD神经发病的关键组成部分。在没有致炎基因上调和神经元损伤的情况下，淀粉样前体蛋白转基因小鼠表现出胶质纤维酸性蛋白和IL-4诱导(p<；0.05)，而PAR2在疾病进展的早期阶段上调。PAR2基因缺陷的小鼠，在海马区Aβ(1-42)植入后，IL-4诱导增强，神经炎症减少(p<；0.05)，神经行为结果改善(p<；0.05)。因此，PAR2在神经元中具有保护作用，但它在胶质细胞中的激活是致病的，因为它分泌神经毒性因子，并抑制导致Aβ(1-42)介导的神经变性的星形细胞抗炎机制。
The proteinase-activated receptors (PARs) are a novel family of G protein-coupled receptors, and their effects in neurodegenerative diseases remain uncertain. Alzheimer's disease (AD) is a neurodegenerative disorder defined by misfolded protein accumulation with concurrent neuroinflammation and neuronal death. We report suppression of proteinase-activated receptor-2 (PAR2) expression in neurons of brains from AD patients, whereas PAR2 expression was increased in proximate glial cells, together with up-regulation of proinflammatory cytokines and chemokines and reduced IL-4 expression (p < 0.05). Glial PAR2 activation increased expression of formyl peptide receptor-2 (p < 0.01), a cognate receptor for a fibrillar 42-aa form of beta-amyloid (A beta(1-42)), enhanced microglia-mediated proinflammatory responses, and suppressed astrocytic IL-4 expression, resulting in neuronal death (p < 0.05). Conversely, neuronal PAR2 activation protected human neurons against the toxic effects of A beta(1-42) (p < 0.05), a key component of AD neuropathogenesis. Amyloid precursor protein-transgenic mice, displayed glial fibrillary acidic protein and IL-4 induction (p < 0.05) in the absence of proinflammatory gene up-regulation and neuronal injury, whereas PAR2 was up-regulated at this early stage of disease progression. PAR2-deficient mice, after hippocampal A beta(1-42) implantation, exhibited enhanced IL-4 induction and less neuroinflammation (p < 0.05), together with improved neurobehavioral outcomes (p < 0.05). Thus, PAR2 exerted protective properties in neurons, but its activation in glia was pathogenic with secretion of neurotoxic factors and suppression of astrocytic anti-inflammatory mechanisms contributing to A beta(1-42)-mediated neurodegeneration.