MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer's disease.
MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer's disease.
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DOI：
10.1007/s00018-015-1992-1
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发表时间：
2016-01
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影响因子：
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通讯作者：
Rivera S
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作者：
Baranger K;Marchalant Y;Bonnet AE;Crouzin N;Carrete A;Paumier JM;Py NA;Bernard A;Bauer C;Charrat E;Moschke K;Seiki M;Vignes M;Lichtenthaler SF;Checler F;Khrestchatisky M;Rivera S
膜型5-基质金属蛋白酶（MT5-MMP）是一种主要在神经系统中表达的蛋白酶，在脑病理生理学中具有新兴作用。MT5-MMP在阿尔茨海默病（AD）中的意义，特别是其与淀粉样蛋白生成过程的相互作用，仍然难以捉摸。因此，我们将AD的基因工程5xFAD小鼠模型与MT5-MMP缺陷小鼠杂交，并检查了MT5-MMP缺陷对双基因5xFAD/MT5-MMP−/−小鼠的影响。在病理学的早期阶段（4个月），5xFAD/MT 5-MMP-/-的皮质和海马中淀粉样β肽（Aβ）及其淀粉样前体蛋白（APP）C末端片段C99的水平大幅降低。与5xFAD小鼠相比。双基因小鼠中淀粉样变性的减少伴随着胶质反应性和白细胞介素-1 β（IL-1β）水平的降低，以及长时程增强（LTP）和空间学习的保留，而α-，β-和γ-分泌酶的活性没有变化。MT5-MMP缺陷的积极影响在16个月大时仍然明显，如通过减少淀粉样蛋白负荷和神经胶质增生以及更好地保存双基因小鼠中的皮质神经元网络和突触素水平所示。在HEKswe细胞中表达的MT5-MMP与APP共定位和共免疫沉淀，并显著增加Aβ和C99的水平。MT5-MMP还促进HEKswe细胞中可溶性APP片段95 kDa（sAPP 95）的释放。在5xFAD/MT5-MMP−/−小鼠的脑匀浆中，sAPP 95水平显著降低，这完全支持MT5-MMP影响APP加工的观点。MT5-MMP作为APP代谢的一种新的促淀粉样蛋白生成调节剂出现，其缺乏会加重淀粉样蛋白病理、神经炎症和认知能力下降。本文的在线版本（doi：10.1007/s 00018 -015-1992-1）包含补充材料，可供授权用户使用。
Membrane-type 5-matrix metalloproteinase (MT5-MMP) is a proteinase mainly expressed in the nervous system with emerging roles in brain pathophysiology. The implication of MT5-MMP in Alzheimer’s disease (AD), notably its interplay with the amyloidogenic process, remains elusive. Accordingly, we crossed the genetically engineered 5xFAD mouse model of AD with MT5-MMP-deficient mice and examined the impact of MT5-MMP deficiency in bigenic 5xFAD/MT5-MMP−/− mice. At early stages (4 months) of the pathology, the levels of amyloid beta peptide (Aβ) and its amyloid precursor protein (APP) C-terminal fragment C99 were largely reduced in the cortex and hippocampus of 5xFAD/MT5-MMP−/−, compared to 5xFAD mice. Reduced amyloidosis in bigenic mice was concomitant with decreased glial reactivity and interleukin-1β (IL-1β) levels, and the preservation of long-term potentiation (LTP) and spatial learning, without changes in the activity of α-, β- and γ-secretases. The positive impact of MT5-MMP deficiency was still noticeable at 16 months of age, as illustrated by reduced amyloid burden and gliosis, and a better preservation of the cortical neuronal network and synaptophysin levels in bigenic mice. MT5-MMP expressed in HEKswe cells colocalized and co-immunoprecipitated with APP and significantly increased the levels of Aβ and C99. MT5-MMP also promoted the release of a soluble APP fragment of 95 kDa (sAPP95) in HEKswe cells. sAPP95 levels were significantly reduced in brain homogenates of 5xFAD/MT5-MMP−/− mice, supporting altogether the idea that MT5-MMP influences APP processing. MT5-MMP emerges as a new pro-amyloidogenic regulator of APP metabolism, whose deficiency alleviates amyloid pathology, neuroinflammation and cognitive decline. The online version of this article (doi:10.1007/s00018-015-1992-1) contains supplementary material, which is available to authorized users.